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Verrender A, Wallace NK, Loughran SP, Wallace C, Beange J, Croft RJ. What is the effect of alarmist media and radiofrequency electromagnetic field (RF-EMF) exposure on salivary cortisol and non-specific symptoms? Appl Psychol Health Well Being 2025; 17:e70044. [PMID: 40432371 DOI: 10.1111/aphw.70044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 05/04/2025] [Indexed: 05/29/2025]
Abstract
While there is consistent evidence that the symptoms reported by people who experience Idiopathic Environmental Intolerance attributed to Electromagnetic Fields (IEI-EMF) are closely associated with a nocebo effect, and that alarmist media reports may contribute to this nocebo effect, some methodological criticisms remain to be resolved. This study aimed to replicate previous findings and determine whether viewing an alarmist media report and being openly exposed to radiofrequency electromagnetic fields (RF-EMF) could induce a salivary cortisol response. A total of 144 participants were randomly assigned to watch either an alarmist or control video before completing an open-label provocation trial where they were either exposed or not exposed to RF-EMF. Personality factors, RF-EMF risk perception (pre- and post-video), symptoms and salivary cortisol were assessed. Consistent with previous studies, participants who were aware that they were being exposed had increased symptoms compared to participants who were aware they were not being exposed. However, the current study failed to replicate an effect of viewing an alarmist media report and being openly exposed to RF-EMF on symptoms and failed to identify an effect on salivary cortisol. This suggests that awareness and belief of exposure play a more important role in symptom perception than underlying physiological processes.
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Affiliation(s)
- Adam Verrender
- Australian Centre for Electromagnetic Bioeffects Research, Wollongong, Australia
- School of Psychology, Faculty of Arts, Social Sciences, and Humanities, University of Wollongong, Wollongong, Australia
| | - Nikkeah K Wallace
- Australian Centre for Electromagnetic Bioeffects Research, Wollongong, Australia
- School of Psychology, Faculty of Arts, Social Sciences, and Humanities, University of Wollongong, Wollongong, Australia
| | - Sarah P Loughran
- Australian Centre for Electromagnetic Bioeffects Research, Wollongong, Australia
- School of Psychology, Faculty of Arts, Social Sciences, and Humanities, University of Wollongong, Wollongong, Australia
- Australian Radiation Protection and Nuclear Safety Agency, Yallambie, Australia
| | - Chloe Wallace
- School of Psychology, Faculty of Arts, Social Sciences, and Humanities, University of Wollongong, Wollongong, Australia
| | - James Beange
- School of Psychology, Faculty of Arts, Social Sciences, and Humanities, University of Wollongong, Wollongong, Australia
| | - Rodney J Croft
- Australian Centre for Electromagnetic Bioeffects Research, Wollongong, Australia
- School of Psychology, Faculty of Arts, Social Sciences, and Humanities, University of Wollongong, Wollongong, Australia
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Asim M, Wang H, Waris A, Qianqian G, Chen X. Cholecystokinin neurotransmission in the central nervous system: Insights into its role in health and disease. Biofactors 2024; 50:1060-1075. [PMID: 38777339 PMCID: PMC11627476 DOI: 10.1002/biof.2081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 05/08/2024] [Indexed: 05/25/2024]
Abstract
Cholecystokinin (CCK) plays a key role in various brain functions, including both health and disease states. Despite the extensive research conducted on CCK, there remain several important questions regarding its specific role in the brain. As a result, the existing body of literature on the subject is complex and sometimes conflicting. The primary objective of this review article is to provide a comprehensive overview of recent advancements in understanding the central nervous system role of CCK, with a specific emphasis on elucidating CCK's mechanisms for neuroplasticity, exploring its interactions with other neurotransmitters, and discussing its significant involvement in neurological disorders. Studies demonstrate that CCK mediates both inhibitory long-term potentiation (iLTP) and excitatory long-term potentiation (eLTP) in the brain. Activation of the GPR173 receptor could facilitate iLTP, while the Cholecystokinin B receptor (CCKBR) facilitates eLTP. CCK receptors' expression on different neurons regulates activity, neurotransmitter release, and plasticity, emphasizing CCK's role in modulating brain function. Furthermore, CCK plays a pivotal role in modulating emotional states, Alzheimer's disease, addiction, schizophrenia, and epileptic conditions. Targeting CCK cell types and circuits holds promise as a therapeutic strategy for alleviating these brain disorders.
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Affiliation(s)
- Muhammad Asim
- Department of NeuroscienceCity University of Hong KongKowloon TongHong Kong
- Department of Biomedical ScienceCity University of Hong KongKowloon TongHong Kong
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Chinese Academy of SciencesPak Shek KokHong Kong
| | - Huajie Wang
- Department of NeuroscienceCity University of Hong KongKowloon TongHong Kong
| | - Abdul Waris
- Department of Biomedical ScienceCity University of Hong KongKowloon TongHong Kong
| | - Gao Qianqian
- Department of NeuroscienceCity University of Hong KongKowloon TongHong Kong
| | - Xi Chen
- Department of NeuroscienceCity University of Hong KongKowloon TongHong Kong
- Department of Biomedical ScienceCity University of Hong KongKowloon TongHong Kong
- Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Chinese Academy of SciencesPak Shek KokHong Kong
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Fahed R, Schulz C, Klaus J, Ellinger S, Walter M, Kroemer NB. Ghrelin is associated with an elevated mood after an overnight fast in depression. J Psychiatr Res 2024; 175:271-279. [PMID: 38759494 DOI: 10.1016/j.jpsychires.2024.04.053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 03/26/2024] [Accepted: 04/28/2024] [Indexed: 05/19/2024]
Abstract
BACKGROUND Major depressive disorder (MDD) comprises subtypes with distinct symptom profiles. For example, patients with melancholic and atypical MDD differ in the direction of appetite and body weight changes as well as mood reactivity. Despite reported links to altered energy metabolism, the role of circulating neuropeptides from the gut in modulating such symptoms remains largely elusive. METHODS We collected data from 103 participants, including 52 patients with MDD and 51 healthy control participants (HCP). After an overnight fast, we measured plasma levels of (acyl and des-acyl) ghrelin and participants reported their current metabolic and mood states using visual analog scales (VAS). Furthermore, they completed symptom-related questionnaires (i.e., STAI-T). RESULTS Patients with atypical versus melancholic MDD reported less negative affect (p = 0.025). Higher levels of acyl ghrelin (corrected for BMI) were associated with improved mood (p = 0.012), specifically in patients with MDD. These associations of ghrelin were not mood-item specific and exceeded correlations with trait markers of negative affectivity. In contrast to associations with mood state, higher levels of ghrelin were not associated with increased hunger per se or changes in appetite in patients with MDD. LIMITATIONS The study is limited by the cross-sectional design without an intervention. CONCLUSIONS Our results reveal potentially mood-enhancing effects of ghrelin in fasting individuals that exceed associations with metabolic state ratings. These associations with circulating neuropeptides might help explain anti-depressive effects of fasting interventions and could complement conventional treatments in patients with melancholic MDD.
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Affiliation(s)
- Rauda Fahed
- Department of Psychiatry and Psychotherapy, Tübingen Center for Mental Health, University of Tübingen, Tübingen, Germany
| | - Corinna Schulz
- Department of Psychiatry and Psychotherapy, Tübingen Center for Mental Health, University of Tübingen, Tübingen, Germany
| | - Johannes Klaus
- Department of Psychiatry and Psychotherapy, Tübingen Center for Mental Health, University of Tübingen, Tübingen, Germany; German Center for Mental Health (DZPG), partner site Tübingen, Germany
| | - Sabine Ellinger
- Institute of Nutritional and Food Sciences, Human Nutrition, University of Bonn, Bonn, Germany
| | - Martin Walter
- Department of Psychiatry and Psychotherapy, Tübingen Center for Mental Health, University of Tübingen, Tübingen, Germany; Department of Psychiatry and Psychotherapy, University Hospital Jena, Jena, Germany; Department of Psychiatry and Psychotherapy, Otto-von-Guericke University Magdeburg, Magdeburg, Germany; German Center for Mental Health (DZPG), partner site Halle-Jena-Magdeburg, Germany
| | - Nils B Kroemer
- Section of Medical Psychology, Department of Psychiatry and Psychotherapy, Faculty of Medicine, University of Bonn, Bonn, Germany; Department of Psychiatry and Psychotherapy, Tübingen Center for Mental Health, University of Tübingen, Tübingen, Germany; German Center for Mental Health (DZPG), partner site Tübingen, Germany.
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Liu FS, Wang S, Guo XS, Ye ZX, Zhang HY, Li Z. State of art on the mechanisms of laparoscopic sleeve gastrectomy in treating type 2 diabetes mellitus. World J Diabetes 2023; 14:632-655. [PMID: 37383590 PMCID: PMC10294061 DOI: 10.4239/wjd.v14.i6.632] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 04/01/2023] [Accepted: 04/24/2023] [Indexed: 06/14/2023] Open
Abstract
Obesity and type-2 diabetes mellitus (T2DM) are metabolic disorders. Obesity increases the risk of T2DM, and as obesity is becoming increasingly common, more individuals suffer from T2DM, which poses a considerable burden on health systems. Traditionally, pharmaceutical therapy together with lifestyle changes is used to treat obesity and T2DM to decrease the incidence of comorbidities and all-cause mortality and to increase life expectancy. Bariatric surgery is increasingly replacing other forms of treatment of morbid obesity, especially in patients with refractory obesity, owing to its many benefits including good long-term outcomes and almost no weight regain. The bariatric surgery options have markedly changed recently, and laparoscopic sleeve gastrectomy (LSG) is gradually gaining popularity. LSG has become an effective and safe treatment for type-2 diabetes and morbid obesity, with a high cost-benefit ratio. Here, we review the me-chanism associated with LSG treatment of T2DM, and we discuss clinical studies and animal experiments with regard to gastrointestinal hormones, gut microbiota, bile acids, and adipokines to clarify current treatment modalities for patients with obesity and T2DM.
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Affiliation(s)
- Fa-Shun Liu
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Song Wang
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Xian-Shan Guo
- Department of Endocrinology, Xinxiang Central Hospital, Xinxiang 453000, Henan Province, China
| | - Zhen-Xiong Ye
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Hong-Ya Zhang
- Central Laboratory, Yangpu District Control and Prevention Center, Shanghai 200090, China
| | - Zhen Li
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
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Wu Y, Zhao Y, Wu L, Zhang P, Yu G. Non-Pharmacological Management for Vaccine-Related Pain in Children in the Healthcare Setting: A Scoping Review. J Pain Res 2022; 15:2773-2782. [PMID: 36106315 PMCID: PMC9467445 DOI: 10.2147/jpr.s371797] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 08/05/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose To examine how research was conducted on non-pharmacological management in children with vaccine-related pain in the healthcare setting, so as to provide reference for the relief of vaccine-related pain in children. Methods This study conducted a scoping review guided by the methodological framework of Arksey and O'Malley. MEDLINE, Cochrane Library, EMBASE, CINAHL, PubMed databases were searched in detail, and search strategy included the keyword "vaccine", the keyword "pain", and the keyword "children". Two researchers conducted literature screening and data extraction independently, and any disagreements were resolved through team consultation. Results This study retrieved 1017 literatures, of which 22 were finally included, including 18 randomized controlled studies, 3 quasi-experimental studies and 1 cohort study. Non-pharmacological management measures were summarized in the study, mainly involving taste, tactile, olfactory, visual, exercise, and postural interventions and injection technique. All the above non-pharmacological management were effective in mitigating vaccine-related pain in children. The study population in the included literatures was mainly neonates and infants. Regarding the analgesic effects of taste intervention, breastfeeding was better than sweeteners, and sweeteners were better than sterile water or non-nutritive sucking. However, there was a lack of comparative studies on the analgesic effects of other non-pharmacological management. Conclusion There are many non-pharmacological management measures with varying analgesic effects. Diversified non-pharmacological management measures can provide more analgesic choices for children. For reducing vaccine-related pain in newborns and infants, breastfeeding is recommended first, then sweeteners, and then non-nutritious sucking. In addition to the taste intervention, the analgesic effects of other non-pharmacological management measures need further comparative studies. Moreover, medical staff can use a combination of non-pharmacological analgesic measures to maximize the analgesic effect, and medical staff should also fully consider the analgesia willingness of children and parents.
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Affiliation(s)
- Yujie Wu
- Department of Nursing, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
| | - Yong Zhao
- School of Public Health and Management, Chongqing Medical University, Chongqing, 400014, People’s Republic of China
| | - Liping Wu
- Department of Nursing, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, People’s Republic of China
| | - Ping Zhang
- Department of Nursing, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
| | - Genzhen Yu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China
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Fiorio M, Braga M, Marotta A, Villa-Sánchez B, Edwards MJ, Tinazzi M, Barbiani D. Functional neurological disorder and placebo and nocebo effects: shared mechanisms. Nat Rev Neurol 2022; 18:624-635. [PMID: 36075980 DOI: 10.1038/s41582-022-00711-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/04/2022] [Indexed: 11/09/2022]
Abstract
Functional neurological disorder (FND) is characterized by neurological symptoms that cannot be explained by a structural neurological cause. Among the different aetiological models that have been proposed for FND, of note is the Bayesian predictive coding model, which posits that perception relies on top-down cortical predictions (priors) to infer the source of incoming sensory information. This model can also apply to non-pathological experiences, such as placebo and nocebo effects, wherein sensory information is shaped by prior expectations and learning. To date, most studies of the relationship between placebo and nocebo effects and FND have focused on the use of placebos for diagnosis and treatment of FND. Here, we propose that this relationship might go beyond diagnosis and therapy. We develop a framework in which shared cognitive, personality and neuroanatomical factors justify the consideration of a deeper link between FND and placebo and nocebo effects. This new perspective might offer guidance for clarification of the pathogenesis of FND and for the identification of potential biomarkers and therapeutic targets.
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Affiliation(s)
- Mirta Fiorio
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
| | - Miriam Braga
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Angela Marotta
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | | | - Mark J Edwards
- Institute of Molecular and Clinical Sciences, St George's University of London, London, UK
| | - Michele Tinazzi
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Diletta Barbiani
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
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Ma Y, Giardino WJ. Neural circuit mechanisms of the cholecystokinin (CCK) neuropeptide system in addiction. ADDICTION NEUROSCIENCE 2022; 3:100024. [PMID: 35983578 PMCID: PMC9380858 DOI: 10.1016/j.addicn.2022.100024] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Given historical focus on the roles for cholecystokinin (CCK) as a peripheral hormone controlling gastrointestinal processes and a brainstem peptide regulating food intake, the study of CCK as a limbic neuromodulator coordinating reward-seeking and emotional behavior remains underappreciated. Furthermore, localization of CCK to specialized interneurons throughout the hippocampus and cortex relegated CCK to being examined primarily as a static cell type marker rather than a dynamic functional neuromodulator. Yet, over three decades of literature have been generated by efforts to delineate the central mechanisms of addiction-related behaviors mediated by the CCK system across the striatum, amygdala, hypothalamus, and midbrain. Here, we cover fundamental findings that implicate CCK neuron activity and CCK receptor signaling in modulating drug intake and drug-seeking (focusing on psychostimulants, opioids, and alcohol). In doing so, we highlight the few studies that indicate sex differences in CCK expression and corresponding drug effects, emphasizing the importance of examining hormonal influences and sex as a biological variable in translating basic science discoveries to effective treatments for substance use disorders in human patients. Finally, we point toward understudied subcortical sources of endogenous CCK and describe how continued neurotechnology advancements can be leveraged to modernize understanding of the neural circuit mechanisms underlying CCK release and signaling in addiction-relevant behaviors.
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Affiliation(s)
- Yihe Ma
- Department of Psychiatry & Behavioral Sciences and Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - William J. Giardino
- Department of Psychiatry & Behavioral Sciences and Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, USA
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Dai W, Liu J, Qiu Y, Teng Z, Li S, Yuan H, Huang J, Xiang H, Tang H, Wang B, Chen J, Wu H. Gut Microbial Dysbiosis and Cognitive Impairment in Bipolar Disorder: Current Evidence. Front Pharmacol 2022; 13:893567. [PMID: 35677440 PMCID: PMC9168430 DOI: 10.3389/fphar.2022.893567] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 04/20/2022] [Indexed: 12/11/2022] Open
Abstract
Recent studies have reported that the gut microbiota influences mood and cognitive function through the gut-brain axis, which is involved in the pathophysiology of neurocognitive and mental disorders, including Parkinson’s disease, Alzheimer’s disease, and schizophrenia. These disorders have similar pathophysiology to that of cognitive dysfunction in bipolar disorder (BD), including neuroinflammation and dysregulation of various neurotransmitters (i.e., serotonin and dopamine). There is also emerging evidence of alterations in the gut microbial composition of patients with BD, suggesting that gut microbial dysbiosis contributes to disease progression and cognitive impairment in BD. Therefore, microbiota-centered treatment might be an effective adjuvant therapy for BD-related cognitive impairment. Given that studies focusing on connections between the gut microbiota and BD-related cognitive impairment are lagging behind those on other neurocognitive disorders, this review sought to explore the potential mechanisms of how gut microbial dysbiosis affects cognitive function in BD and identify potential microbiota-centered treatment.
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Affiliation(s)
- Wenyu Dai
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Jieyu Liu
- Department of Ultrasound Diagnostic, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yan Qiu
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Ziwei Teng
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Sujuan Li
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Hui Yuan
- Department of Ultrasound Diagnostic, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Jing Huang
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Hui Xiang
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Hui Tang
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Bolun Wang
- Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Jindong Chen
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Haishan Wu
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
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Keller BN, Hajnal A, Browning KN, Arnold AC, Silberman Y. Involvement of the Dorsal Vagal Complex in Alcohol-Related Behaviors. Front Behav Neurosci 2022; 16:801825. [PMID: 35330845 PMCID: PMC8940294 DOI: 10.3389/fnbeh.2022.801825] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 01/19/2022] [Indexed: 12/20/2022] Open
Abstract
The neurobiological mechanisms that regulate the development and maintenance of alcohol use disorder (AUD) are complex and involve a wide variety of within and between systems neuroadaptations. While classic reward, preoccupation, and withdrawal neurocircuits have been heavily studied in terms of AUD, viable treatment targets from this established literature have not proven clinically effective as of yet. Therefore, examination of additional neurocircuitries not classically studied in the context of AUD may provide novel therapeutic targets. Recent studies demonstrate that various neuropeptides systems are important modulators of alcohol reward, seeking, and intake behaviors. This includes neurocircuitry within the dorsal vagal complex (DVC), which is involved in the control of the autonomic nervous system, control of intake of natural rewards like food, and acts as a relay of interoceptive sensory information via interactions of numerous gut-brain peptides and neurotransmitter systems with DVC projections to central and peripheral targets. DVC neuron subtypes produce a variety of neuropeptides and transmitters and project to target brain regions critical for reward such as the mesolimbic dopamine system as well as other limbic areas important for the negative reinforcing and aversive properties of alcohol withdrawal such as the extended amygdala. This suggests the DVC may play a role in the modulation of various aspects of AUD. This review summarizes the current literature on neurotransmitters and neuropeptides systems in the DVC (e.g., norepinephrine, glucagon-like peptide 1, neurotensin, cholecystokinin, thyrotropin-releasing hormone), and their potential relevance to alcohol-related behaviors in humans and rodent models for AUD research. A better understanding of the role of the DVC in modulating alcohol related behaviors may lead to the elucidation of novel therapeutic targets for drug development in AUD.
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Exploring the role of neuropeptides in depression and anxiety. Prog Neuropsychopharmacol Biol Psychiatry 2022; 114:110478. [PMID: 34801611 DOI: 10.1016/j.pnpbp.2021.110478] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 11/13/2021] [Accepted: 11/13/2021] [Indexed: 12/24/2022]
Abstract
Depression is one of the most prevalent forms of mental disorders and is the most common cause of disability in the Western world. Besides, the harmful effects of stress-related mood disorders on the patients themselves, they challenge the health care system with enormous social and economic impacts. Due to the high proportion of patients not responding to existing drugs, finding new treatment strategies has become an important topic in neurobiology, and there is much evidence that neuropeptides are not only involved in the physiology of stress but may also be clinically important. Based on preclinical trial data, new neuropharmaceutical candidates may target neuropeptides and their receptors and are expected to be essential and valuable tools in the treatment of psychiatric disorders. In the current article, we have summarized data obtained from animal models of depressive disorder and transgenic mouse models. We also focus on previously published research data of clinical studies on corticotropin-releasing hormone (CRH), galanin (GAL), neuropeptide Y (NPY), neuropeptide S (NPS), Oxytocin (OXT), vasopressin (VP), cholecystokinin (CCK), and melanin-concentrating hormone (MCH) stress research fields.
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12
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Espinosa Fernández MG, González-Pacheco N, Sánchez-Redondo MD, Cernada M, Martín A, Pérez-Muñuzuri A, Boix H, Couce ML. Sedoanalgesia in neonatal units. An Pediatr (Barc) 2021; 95:126.e1-126.e11. [PMID: 34332948 DOI: 10.1016/j.anpede.2020.10.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 10/09/2020] [Indexed: 12/27/2022] Open
Abstract
Pain recognition and management continues to be a challenge for health professionals in Neonatal Intensive Care Units. Many of the patients are routinely exposed to repeated painful experiences with demonstrated short- and long-term consequences. Preterm babies are a vulnerable high-risk population. Despite international recommendations, pain remains poorly assessed and managed in many Neonatal Intensive Care Units. Due to there being no general protocol, there is significant variability as regards the guidelines for the approach and treatment of pain between the different Neonatal Intensive Care Units. The objective of this article is to review and assess the general principles of pain in the initial stages of development, its recognition through the use of standardised scales. It also includes its prevention and management with the combination of pharmacological and non-pharmacological measures, as well as to establish recommendations that help alleviate pain in daily clinical practice by optimising pain and stress control in the Neonatal Intensive Care Units.
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Affiliation(s)
| | | | | | - María Cernada
- Servicio de Neonatología, Hospital Universitario y Politécnico La Fe, Grupo de Investigación en Perinatología, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - Ana Martín
- Servicio de Neonatología, Hospital Sant Joan de Deu, Barcelona, Spain
| | - Alejandro Pérez-Muñuzuri
- Servicio de Neonatología, Hospital Clínico Universitario de Santiago, IDIS, Universidad de Santiago de Compostela, Santiago de Compostela, Spain
| | - Hector Boix
- Servicio de Neonatología, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - María L Couce
- Servicio de Neonatología, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
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13
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Zhang Y, Zhang H, Jiang B, Tong X, Yan S, Lu J. Current views on neuropeptides in atopic dermatitis. Exp Dermatol 2021; 30:1588-1597. [PMID: 33963624 DOI: 10.1111/exd.14382] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/24/2021] [Accepted: 04/26/2021] [Indexed: 12/19/2022]
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease involving skin barrier dysfunction and immune imbalance. However, the mechanism of AD is not clear completely and may be related to heredity and environment. Neuropeptides are a class of peptides secreted by nerve endings, they may play roles in promoting vasodilation, plasma extravasation, chemotaxis of inflammatory cells and mediating pruritus. Since itching and immune cell infiltration are the main manifestations of atopic dermatitis, to further investigate the impact of neuropeptides on AD, our review summarized the mechanisms of several common neuropeptides in AD and hypothesized that neuropeptides may be the novel potential targets in AD treatment.
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Affiliation(s)
- Yue Zhang
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, China.,Xiangya School of Medicine, Central South University, Changsha, China
| | - Hanyi Zhang
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, China.,Xiangya School of Medicine, Central South University, Changsha, China
| | - Boyue Jiang
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, China.,Xiangya School of Medicine, Central South University, Changsha, China
| | - Xiaoliang Tong
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Siyu Yan
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Jianyun Lu
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, China
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Ballaz S, Espinosa N, Bourin M. Does endogenous cholecystokinin modulate alcohol intake? Neuropharmacology 2021; 193:108539. [PMID: 33794246 DOI: 10.1016/j.neuropharm.2021.108539] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 02/06/2021] [Accepted: 03/22/2021] [Indexed: 02/08/2023]
Abstract
Alcohol use disorder or alcoholism is characterized by uncontrollable alcohol use and intoxication, as well as a heightened state of anxiety after alcohol withdrawal. Ethanol-associated stimuli also drive the urge to drink by means of classical conditioning. Alcoholism has been considered a dopamine (DA) dysregulation syndrome that involves the activity of the central amygdala circuitry of anxiety. Cholecystokinin (CCK) is the most abundant neuropeptide in the mammal brain, where it activates two receptors, CCK1 and CCK2. Genetic evidence relates CCK1 receptors to alcoholism in humans. CCK2 activity has been associated with the onset of human anxiety. CCK modulates DA release in the nucleus accumbens (NAc) and it is expressed in the γ-aminobutyric acid (GABA)-expressing basket interneurons in the cerebral cortex. CCK interacts with serotonin (5-HT) neurotransmission through 5-HT3 receptors to regulate mesocorticolimbic pathways and with GABA to attenuate anxiety in the amygdala. Finally, CCK stimulates the release of orexins and oxytocin in the hypothalamus, two relevant hypothalamic neuropeptides involved in signaling satiety for ethanol and well-being respectively. Given the "dimmer-switch" function of endogenous CCK in the neurotransmission by 5-HT, DA, GABA, and glutamate in normal and pathological behaviors (Ballaz and Bourin, 2020), we hypothesize that CCK adjusts functioning of the reward and anxiety circuitries altered by ethanol. This review gathers data supporting this hypothesis, and suggests mechanisms underlying a role for endogenous CCK in alcoholism.
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Affiliation(s)
- Santiago Ballaz
- School of Biological Sciences & Engineering, Yachay Tech University, Hacienda San José s/n, San Miguel de Urcuquí, Ecuador; School of Medicine, Universidad Espíritu Santo, Samborondón, Ecuador.
| | - Nicole Espinosa
- School of Biological Sciences & Engineering, Yachay Tech University, Hacienda San José s/n, San Miguel de Urcuquí, Ecuador.
| | - Michel Bourin
- Neurobiology of Anxiety and Mood Disorders, University of Nantes, 98, Rue Joseph Blanchart, 44100 Nantes, France.
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15
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Isaac L, van den Hoogen NJ, Habib S, Trang T. Maternal and iatrogenic neonatal opioid withdrawal syndrome: Differences and similarities in recognition, management, and consequences. J Neurosci Res 2021; 100:373-395. [PMID: 33675100 DOI: 10.1002/jnr.24811] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 02/01/2021] [Indexed: 11/12/2022]
Abstract
Opioids are potent analgesics used to manage pain in both young and old, but the increased use in the pregnant population has significant individual and societal implications. Infants dependent on opioids, either through maternal or iatrogenic exposure, undergo neonatal opioid withdrawal syndrome (NOWS), where they may experience withdrawal symptoms ranging from mild to severe. We present a detailed and original review of NOWS caused by maternal opioid exposure (mNOWS) and iatrogenic opioid intake (iNOWS). While these two entities have been assessed entirely separately, recognition and treatment of the clinical manifestations of NOWS overlap. Neonatal risk factors such as age, genetic predisposition, drug type, and clinical factors like type of opioid, cumulative dose of opioid exposure, and disease status affect the incidence of both mNOWS and iNOWS, as well as their severity. Recognition of withdrawal is dependent on clinical assessment of symptoms, and the use of clinical assessment tools designed to determine the need for pharmacotherapy. Treatment of NOWS relies on a combination of non-pharmacological therapies and pharmacological options. Long-term consequences of opioids and NOWS continue to generate controversy, with some evidence of anatomic brain changes, but conflicting animal and human clinical evidence of significant cognitive or behavioral impacts on school-age children. We highlight the current knowledge on clinically relevant recognition, treatment, and consequences of NOWS, and identify new advances in clinical management of the neonate. This review brings a unique clinical perspective and critically analyzes gaps between the clinical problem and our preclinical understanding of NOWS.
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Affiliation(s)
- Lisa Isaac
- Department of Anesthesia and Pain Medicine, Hospital for Sick Children, Toronto, ON, Canada.,Department of Anesthesiology and Pain Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Nynke J van den Hoogen
- Comparative Biology and Experimental Medicine, Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Toronto, ON, Canada
| | - Sharifa Habib
- Department of Neonatology, Hospital for Sick Children, Toronto, ON, Canada.,Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Toronto, ON, Canada
| | - Tuan Trang
- Comparative Biology and Experimental Medicine, Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Toronto, ON, Canada
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16
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Ballaz SJ, Bourin M. Cholecystokinin-Mediated Neuromodulation of Anxiety and Schizophrenia: A "Dimmer-Switch" Hypothesis. Curr Neuropharmacol 2021; 19:925-938. [PMID: 33185164 PMCID: PMC8686311 DOI: 10.2174/1570159x18666201113145143] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 10/08/2020] [Accepted: 11/10/2020] [Indexed: 11/22/2022] Open
Abstract
Cholecystokinin (CCK), the most abundant brain neuropeptide, is involved in relevant behavioral functions like memory, cognition, and reward through its interactions with the opioid and dopaminergic systems in the limbic system. CCK excites neurons by binding two receptors, CCK1 and CCK2, expressed at low and high levels in the brain, respectively. Historically, CCK2 receptors have been related to the induction of panic attacks in humans. Disturbances in brain CCK expression also underlie the physiopathology of schizophrenia, which is attributed to the modulation by CCK1 receptors of the dopamine flux in the basal striatum. Despite this evidence, neither CCK2 receptor antagonists ameliorate human anxiety nor CCK agonists have consistently shown neuroleptic effects in clinical trials. A neglected aspect of the function of brain CCK is its neuromodulatory role in mental disorders. Interestingly, CCK is expressed in pivotal inhibitory interneurons that sculpt cortical dynamics and the flux of nerve impulses across corticolimbic areas and the excitatory projections to mesolimbic pathways. At the basal striatum, CCK modulates the excitability of glutamate, the release of inhibitory GABA, and the discharge of dopamine. Here we focus on how CCK may reduce rather than trigger anxiety by regulating its cognitive component. Adequate levels of CCK release in the basal striatum may control the interplay between cognition and reward circuitry, which is critical in schizophrenia. Hence, it is proposed that disturbances in the excitatory/ inhibitory interplay modulated by CCK may contribute to the imbalanced interaction between corticolimbic and mesolimbic neural activity found in anxiety and schizophrenia.
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Affiliation(s)
- Santiago J. Ballaz
- Address correspondence to this author at the School of Biological Sciences & Engineering, Yachay Tech University, Hacienda San José s/n, San Miguel de Urcuquí, Ecuador; Tel: 593 (06) 299 9100, ext. 2626; E-mail:
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17
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Hammack SE, Braas KM, May V. Chemoarchitecture of the bed nucleus of the stria terminalis: Neurophenotypic diversity and function. HANDBOOK OF CLINICAL NEUROLOGY 2021; 179:385-402. [PMID: 34225977 DOI: 10.1016/b978-0-12-819975-6.00025-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The bed nucleus of the stria terminalis (BNST) is a compact but neurophenotypically complex structure in the ventral forebrain that is structurally and functionally linked to other limbic structures, including the amygdala nuclear complex, hypothalamic nuclei, hippocampus, and related midbrain structures, to participate in a wide range of functions, especially emotion, emotional learning, stress-related responses, and sexual behaviors. From a variety of sensory inputs, the BNST acts as a node for signal integration and coordination for information relay to downstream central neuroendocrine and autonomic centers for appropriate homeostatic physiological and behavioral responses. In contrast to the role of the amygdala in fear, the BNST has gained wide interest from work suggesting that it has main roles in mediating sustained responses to diffuse, unpredictable and/or long-duration threats that are typically associated with anxiety-related responses. Further, some BNST subregions are highly sexually dimorphic which appear contributory to the differential stress and social interactive behaviors, including reproductive responses, between males and females. Notably, maladaptive BNST neuroplasticity and function have been implicated in chronic pain, depression, anxiety-related abnormalities, and other psychopathologies including posttraumatic stress disorders. The BNST circuits are predominantly GABAergic-the glutaminergic neurons represent a minor population-but the complexity of the system results from an overlay of diverse neuropeptide coexpression in these neurons. More than a dozen neuropeptides may be differentially coexpressed in BNST neurons, and from variable G protein-coupled receptor signaling, may inhibit or activate downstream circuit activities. The mechanisms and roles of these peptides in modulating intrinsic BNST neurocircuit signaling and BNST long-distance target cell projections are still not well understood. Nevertheless, an understanding of some of the principal players may allow assembly of the circuit interactions.
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Affiliation(s)
- Sayamwong E Hammack
- Department of Psychological Science, University of Vermont, Burlington, VT, United States
| | - Karen M Braas
- Department of Neurological Sciences, University of Vermont Larner College of Medicine, Burlington, VT, United States
| | - Victor May
- Department of Neurological Sciences, University of Vermont Larner College of Medicine, Burlington, VT, United States.
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18
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Gibula-Tarlowska E, Kotlinska JH. Crosstalk between Opioid and Anti-Opioid Systems: An Overview and Its Possible Therapeutic Significance. Biomolecules 2020; 10:E1376. [PMID: 32998249 PMCID: PMC7599993 DOI: 10.3390/biom10101376] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 09/20/2020] [Accepted: 09/23/2020] [Indexed: 12/23/2022] Open
Abstract
Opioid peptides and receptors are broadly expressed throughout peripheral and central nervous systems and have been the subject of intense long-term investigations. Such studies indicate that some endogenous neuropeptides, called anti-opioids, participate in a homeostatic system that tends to reduce the effects of endogenous and exogenous opioids. Anti-opioid properties have been attributed to various peptides, including melanocyte inhibiting factor (MIF)-related peptides, cholecystokinin (CCK), nociceptin/orphanin FQ (N/OFQ), and neuropeptide FF (NPFF). These peptides counteract some of the acute effects of opioids, and therefore, they are involved in the development of opioid tolerance and addiction. In this work, the anti-opioid profile of endogenous peptides was described, mainly taking into account their inhibitory influence on opioid-induced effects. However, the anti-opioid peptides demonstrated complex properties and could show opioid-like as well as anti-opioid effects. The aim of this review is to detail the phenomenon of crosstalk taking place between opioid and anti-opioid systems at the in vivo pharmacological level and to propose a cellular and molecular basis for these interactions. A better knowledge of these mechanisms has potential therapeutic interest for the control of opioid functions, notably for alleviating pain and/or for the treatment of opioid abuse.
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Affiliation(s)
- Ewa Gibula-Tarlowska
- Department of Pharmacology and Pharmacodynamics, Medical University, 20-059 Lublin, Poland;
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19
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Goldstein P, Ashar Y, Tesarz J, Kazgan M, Cetin B, Wager TD. Emerging Clinical Technology: Application of Machine Learning to Chronic Pain Assessments Based on Emotional Body Maps. Neurotherapeutics 2020; 17:774-783. [PMID: 32767227 PMCID: PMC7609511 DOI: 10.1007/s13311-020-00886-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
Depression and anxiety co-occur with chronic pain, and all three are thought to be caused by dysregulation of shared brain systems related to emotional processing associated with body sensations. Understanding the connection between emotional states, pain, and bodily sensations may help understand chronic pain conditions. We developed a mobile platform for measuring pain, emotions, and associated bodily feelings in chronic pain patients in their daily life conditions. Sixty-five chronic back pain patients reported the intensity of their pain, 11 emotional states, and the corresponding body locations. These variables were used to predict pain 2 weeks later. Applying machine learning, we developed two predictive models of future pain, emphasizing interpretability. One model excluded pain-related features as predictors of future pain, and the other included pain-related predictors. The best predictors of future pain were interactive effects of (a) body maps of fatigue with negative affect and (b) positive affect with past pain. Our findings emphasize the contribution of emotions, especially emotional experience felt in the body, to understanding chronic pain above and beyond the mere tracking of pain levels. The results may contribute to the generation of a novel artificial intelligence framework to help in the development of better diagnostic and therapeutic approaches to chronic pain.
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Affiliation(s)
- Pavel Goldstein
- The School of Public Health, University of Haifa, Haifa, Israel.
| | - Yoni Ashar
- Weill Cornell Medical College, New York, NY, USA
| | - Jonas Tesarz
- Department for General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg, Germany
| | | | | | - Tor D Wager
- Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH, USA.
- Institute of Cognitive Science, University of Colorado Boulder, Boulder, CO, USA.
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20
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Royds J, Conroy MJ, Dunne MR, Cassidy H, Matallanas D, Lysaght J, McCrory C. Examination and characterisation of burst spinal cord stimulation on cerebrospinal fluid cellular and protein constituents in patient responders with chronic neuropathic pain - A Pilot Study. J Neuroimmunol 2020; 344:577249. [PMID: 32361148 DOI: 10.1016/j.jneuroim.2020.577249] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 03/11/2020] [Accepted: 04/21/2020] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Patients with neuropathic pain have altered proteomic and neuropeptide constituents in cerebrospinal fluid (CSF) compared to controls. Tonic spinal cord stimulation (SCS) has demonstrated differential expression of neuropeptides in CSF before and after treatment suggesting potential mechanisms of action. Burst-SCS is an evidence-based paraesthesia free waveform utilised for neuropathic pain with a potentially different mechanistic action to tonic SCS. This study examines the dynamic biological changes of CSF at a cellular and proteome level after Burst-SCS. METHODS Patients with neuropathic pain selected for SCS had CSF sampled prior to implant of SCS and following 8 weeks of continuous Burst-SCS. Baseline and 8-week pain scores with demographics were recorded. T cell frequencies were analysed by flow cytometry, proteome analysis was performed using mass spectrometry and secreted cytokines, chemokines and neurotrophins were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS 4 patients (2 females, 2 males) with a mean age of 51 years (+/-SEM 2.74, SD 5.48) achieved a reduction in pain of >50% following 8 weeks of Burst-SCS. Analysis of the CSF proteome indicated a significant alteration in protein expression most related to synapse assembly and immune regulators. There was significantly lower expression of the proteins: growth hormone A1 (PRL), somatostatin (SST), nucleobindin-2 (NUCB2), Calbindin (CALB1), acyl-CoA binding protein (DBI), proSAAS (PCSK1N), endothelin-3 (END3) and cholecystokinin (CCK) after Burst-SCS. The concentrations of secreted chemokines and cytokines and the frequencies of T cells were not significantly changed following Burst-SCS. CONCLUSION This study characterised the alteration in the CSF proteome in response to burst SCS in vivo. Functional analysis indicated that the alterations in the CSF proteome is predominately linked to synapse assembly and immune effectors. Individual protein analysis also suggests potential supraspinal mechanisms.
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Affiliation(s)
- Jonathan Royds
- Department of Pain Medicine, St. James Hospital, Dublin and School of Medicine, Trinity College Dublin, Ireland.
| | - Melissa J Conroy
- Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital and Trinity College Dublin, Dublin 8, Ireland
| | - Margaret R Dunne
- Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital and Trinity College Dublin, Dublin 8, Ireland
| | - Hilary Cassidy
- Systems Biology Ireland, School of Medicine, University College Dublin, Dublin 4, Ireland
| | - David Matallanas
- Systems Biology Ireland, School of Medicine, University College Dublin, Dublin 4, Ireland
| | - Joanne Lysaght
- Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital and Trinity College Dublin, Dublin 8, Ireland
| | - Connail McCrory
- Department of Pain Medicine, St. James Hospital, Dublin and School of Medicine, Trinity College Dublin, Ireland
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21
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Benedetti F, Frisaldi E, Barbiani D, Camerone E, Shaibani A. Nocebo and the contribution of psychosocial factors to the generation of pain. J Neural Transm (Vienna) 2019; 127:687-696. [DOI: 10.1007/s00702-019-02104-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 11/12/2019] [Indexed: 12/17/2022]
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22
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Wang D, Stoveken HM, Zucca S, Dao M, Orlandi C, Song C, Masuho I, Johnston C, Opperman KJ, Giles AC, Gill MS, Lundquist EA, Grill B, Martemyanov KA. Genetic behavioral screen identifies an orphan anti-opioid system. Science 2019; 365:1267-1273. [PMID: 31416932 DOI: 10.1126/science.aau2078] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 02/22/2019] [Accepted: 08/05/2019] [Indexed: 12/12/2022]
Abstract
Opioids target the μ-opioid receptor (MOR) to produce unrivaled pain management, but their addictive properties can lead to severe abuse. We developed a whole-animal behavioral platform for unbiased discovery of genes influencing opioid responsiveness. Using forward genetics in Caenorhabditis elegans, we identified a conserved orphan receptor, GPR139, with anti-opioid activity. GPR139 is coexpressed with MOR in opioid-sensitive brain circuits, binds to MOR, and inhibits signaling to heterotrimeric guanine nucleotide-binding proteins (G proteins). Deletion of GPR139 in mice enhanced opioid-induced inhibition of neuronal firing to modulate morphine-induced analgesia, reward, and withdrawal. Thus, GPR139 could be a useful target for increasing opioid safety. These results also demonstrate the potential of C. elegans as a scalable platform for genetic discovery of G protein-coupled receptor signaling principles.
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Affiliation(s)
- Dandan Wang
- Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Hannah M Stoveken
- Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Stefano Zucca
- Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Maria Dao
- Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Cesare Orlandi
- Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Chenghui Song
- Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Ikuo Masuho
- Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Caitlin Johnston
- Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Karla J Opperman
- Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Andrew C Giles
- Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Matthew S Gill
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Erik A Lundquist
- Department of Molecular Biosciences, The University of Kansas, Lawrence, KS 66045, USA
| | - Brock Grill
- Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
| | - Kirill A Martemyanov
- Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
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Ma F, Wei J, Hao L, Shan Q, Li H, Gao D, Jin Y, Sun P. Bioactive Proteins and their Physiological Functions in Milk. Curr Protein Pept Sci 2019; 20:759-765. [DOI: 10.2174/1389203720666190125104532] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 12/30/2018] [Accepted: 01/12/2019] [Indexed: 11/22/2022]
Abstract
Milk is the basic food for infants and newborn animals, providing a rich source of proteins,
carbohydrates, minerals, and vitamins. Milk also provides nourishment for people of all ages due to its
abundant nutrients, and it is used in the manufacture of numerous health-related products. Milk contains
caseins and whey proteins as the two major protein classes. Caseins fall into four major types
known as αs1-, αs2-, β- and κ-casein, whereas whey proteins comprise a mixture of globular proteins
including β-lactoglobulin, α-lactalbumin, serum albumin, lactoferrin, and other bioactivators. The various
biological activities of these proteins are involved in preventing and treating numerous nutritional,
physiological and metabolic diseases. This article reviews the bioactivities and functions of milk proteins,
which may shed light on future application of milk bioactive substances.
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Affiliation(s)
- Fengtao Ma
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Jingya Wei
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Liyuan Hao
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Qiang Shan
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Hongyang Li
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Duo Gao
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Yuhang Jin
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Peng Sun
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
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Delgado M, Hecht J. A review of the development and functions of cat play, with future research considerations. Appl Anim Behav Sci 2019. [DOI: 10.1016/j.applanim.2019.03.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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A Review of Non-Pharmacological Treatments for Pain Management in Newborn Infants. CHILDREN-BASEL 2018; 5:children5100130. [PMID: 30241352 PMCID: PMC6210323 DOI: 10.3390/children5100130] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 09/05/2018] [Accepted: 09/17/2018] [Indexed: 11/17/2022]
Abstract
Pain is a major problem in sick newborn infants, especially for those needing intensive care. Pharmacological pain relief is the most commonly used, but might be ineffective and has side effects, including long-term neurodevelopmental sequelae. The effectiveness and safety of alternative analgesic methods are ambiguous. The objective was to review the effectiveness and safety of non-pharmacological methods of pain relief in newborn infants and to identify those that are the most effective. PubMed and Google Scholar were searched using the terms: “infant”, “premature”, “pain”, “acupuncture”, “skin-to-skin contact”, “sucrose”, “massage”, “musical therapy” and ‘breastfeeding’. We included 24 studies assessing different methods of non-pharmacological analgesic techniques. Most resulted in some degree of analgesia but many were ineffective and some were even detrimental. Sucrose, for example, was often ineffective but was more effective than music therapy, massage, breast milk (for extremely premature infants) or non-invasive electrical stimulation acupuncture. There were also conflicting results for acupuncture, skin-to-skin care and musical therapy. Most non-pharmacological methods of analgesia provide a modicum of relief for preterm infants, but none are completely effective and there is no clearly superior method. Study is also required to assess potential long-term consequences of any of these methods.
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Yang S, Feng T, Li D, Wen D, Yang C, Ma C, Cong B. CCK-8 Inhibits Acute Morphine-induced Spatial Reference Memory Impairment in Mice. Int J Pept Res Ther 2016. [DOI: 10.1007/s10989-016-9568-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Varga Z, Csabai D, Miseta A, Wiborg O, Czéh B. Chronic stress affects the number of GABAergic neurons in the orbitofrontal cortex of rats. Behav Brain Res 2016; 316:104-114. [PMID: 27555539 DOI: 10.1016/j.bbr.2016.08.030] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 08/08/2016] [Accepted: 08/12/2016] [Indexed: 12/27/2022]
Abstract
Cortical GABAergic dysfunctions have been documented by clinical studies in major depression. We used here an animal model for depression and investigated whether long-term stress exposure can affect the number of GABAergic neurons in the orbitofrontal cortex (OFC). Adult male rats were subjected to 7-weeks of daily stress exposure and behaviorally phenotyped as anhedonic or stress-resilient animals. GABAergic interneurons were identified by immunohistochemistry and systematically quantified. We analyzed calbindin-(CB), calretinin-(CR), cholecystokinin-(CCK), parvalbumin-(PV), neuropeptide Y-(NPY) and somatostatin-positive (SST+) neurons in the following specific subareas of the OFC: medial orbital (MO), ventral orbital (VO), lateral orbital (LO) and dorsolateral orbital (DLO) cortex. For comparison, we also analyzed the primary motor cortex (M1) as a non-limbic cortical area. Stress had a pronounced effect on CB+ neurons and reduced their densities by 40-50% in the MO, VO and DLO. Stress had no effect on CCK+, CR+, PV+, NPY+ and SST+ neurons in any cortical areas. None of the investigated GABAergic neurons were affected by stress in the primary motor cortex. Interestingly, in the stress-resilient animals, we observed a significantly increased density of CCK+ neurons in the VO. NPY+ neuron densities were also significantly different between the anhedonic and stress-resilient rats, but only in the LO. Our present data demonstrate that chronic stress can specifically reduce the density of calbindin-positive GABAergic neurons in the orbitofrontal cortex and suggest that NPY and CCK expression in the OFC may relate to the stress resilience of the animals.
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Affiliation(s)
- Zsófia Varga
- MTA - PTE, Neurobiology of Stress Research Group, Szentágothai Research Center, 7624 Pécs, Hungary
| | - Dávid Csabai
- MTA - PTE, Neurobiology of Stress Research Group, Szentágothai Research Center, 7624 Pécs, Hungary
| | - Attila Miseta
- Department of Laboratory Medicine, University of Pécs, Medical School, 7624 Pécs, Hungary
| | - Ove Wiborg
- Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark
| | - Boldizsár Czéh
- MTA - PTE, Neurobiology of Stress Research Group, Szentágothai Research Center, 7624 Pécs, Hungary; Department of Laboratory Medicine, University of Pécs, Medical School, 7624 Pécs, Hungary; Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark.
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Tinoco A, Valenciano A, Gómez-Boronat M, Blanco A, Nisembaum L, De Pedro N, Delgado M. Two cholecystokinin receptor subtypes are identified in goldfish, being the CCKAR involved in the regulation of intestinal motility. Comp Biochem Physiol A Mol Integr Physiol 2015; 187:193-201. [DOI: 10.1016/j.cbpa.2015.05.027] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Revised: 05/28/2015] [Accepted: 05/31/2015] [Indexed: 12/17/2022]
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LI H, JI X, WEI L. Preparation of Cholecystokinin Molecularly Imprinted Polymer Monolith and its Application in Solid Phase Microextraction and HPLC Analysis. CHINESE JOURNAL OF ANALYTICAL CHEMISTRY 2015. [DOI: 10.1016/s1872-2040(15)60844-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Chen Z, Tang Y, Tao H, Li C, Zhang X, Liu Y. Dynorphin activation of kappa opioid receptor reduces neuronal excitability in the paraventricular nucleus of mouse thalamus. Neuropharmacology 2015; 97:259-69. [PMID: 26056031 DOI: 10.1016/j.neuropharm.2015.05.030] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Revised: 05/25/2015] [Accepted: 05/26/2015] [Indexed: 01/16/2023]
Abstract
It has been reported that kappa opioid receptor (KOR) is expressed in the paraventricular nucleus of thalamus (PVT), a brain region associated with arousal, drug reward and stress. Although intra-PVT infusion of KOR agonist was found to inhibit drug-seeking behavior, it is still unclear whether endogenous KOR agonists directly regulate PVT neuron activity. Here, we investigated the effect of the endogenous KOR agonist dynorphin-A (Dyn-A) on the excitability of mouse PVT neurons at different developmental ages. We found Dyn-A strongly inhibited PVT neurons through a direct postsynaptic hyperpolarization. Under voltage-clamp configuration, Dyn-A evoked an obvious outward current in majority of neurons tested in anterior PVT (aPVT) but only in minority of neurons in posterior PVT (pPVT). The Dyn-A current was abolished by KOR antagonist nor-BNI, Ba(2+) and non-hydrolyzable GDP analogue GDP-β-s, indicating that Dyn-A activates KOR and opens G-protein-coupled inwardly rectifying potassium channels in PVT neurons. More interestingly, by comparing Dyn-A currents in aPVT neurons of mice at various ages, we found Dyn-A evoked significant larger current in aPVT neurons from mice around prepuberty and early puberty stage. In addition, KOR activation by Dyn-A didn't produce obvious desensitization, while mu opioid receptor (MOR) activation induced obvious desensitization of mu receptor itself and also heterologous desensitization of KOR in PVT neurons. Together, our findings indicate that Dyn-A activates KOR and inhibits aPVT neurons in mice at various ages especially around puberty, suggesting a possible role of KOR in regulating aPVT-related brain function including stress response and drug-seeking behavior during adolescence.
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Affiliation(s)
- Zhiheng Chen
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Yamei Tang
- Department of Laboratory, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Huai Tao
- Department of Biochemistry and Molecular Biology, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Cunyan Li
- Department of Laboratory, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Xianghui Zhang
- Mental Health Institute, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Changsha 410011, China
| | - Yong Liu
- Mental Health Institute, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Changsha 410011, China.
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Kim J, Kim Y, Hahm SC, Yoon YW. Effect of the Combination of CI-988 and Morphine on Neuropathic Pain after Spinal Cord Injury in Rats. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2015; 19:125-30. [PMID: 25729274 PMCID: PMC4342732 DOI: 10.4196/kjpp.2015.19.2.125] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Revised: 12/02/2014] [Accepted: 01/03/2015] [Indexed: 11/23/2022]
Abstract
Cholecystokinin is known to be involved in the modulation of nociception and to reduce the efficacy of morphine analgesia. This study investigated the effects of intrathecal administration of morphine and the cholecystokinin type B antagonist CI-988 on below-level neuropathic pain after spinal cord injury in rats. We also examined the interaction of morphine and CI-988 in the antinociceptive effect. Both morphine and CI-988 given individually increased the paw withdrawal threshold to mechanical stimulation in a dose-dependent manner. The combination of ineffective doses of intrathecally administered CI-988 and morphine produced significant analgesic effects and the combination of effective doses resulted in analgesic effects that were greater than the sum of the individual effects of each drug. Thus, morphine showed a synergistic interaction with CI-988 for analgesia of central neuropathic pain.
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Affiliation(s)
- Junesun Kim
- Department of Physical Therapy, Korea University College of Health Science, Seoul 136-703, Korea. ; Rehabilitation Science Program, Korea University College of Health Science, Seoul 136-703, Korea
| | - Youngkyung Kim
- Department of Physiology, Korea University College of Medicine, Seoul 136-705, Korea
| | - Suk-Chan Hahm
- Department of Physical Therapy, Korea University College of Health Science, Seoul 136-703, Korea. ; Rehabilitation Science Program, Korea University College of Health Science, Seoul 136-703, Korea
| | - Young Wook Yoon
- Department of Physiology, Korea University College of Medicine, Seoul 136-705, Korea
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Frisaldi E, Piedimonte A, Benedetti F. Placebo and nocebo effects: a complex interplay between psychological factors and neurochemical networks. AMERICAN JOURNAL OF CLINICAL HYPNOSIS 2015; 57:267-84. [PMID: 25928679 DOI: 10.1080/00029157.2014.976785] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Placebo and nocebo effects have recently emerged as an interesting model to understand some of the intricate underpinnings of the mind-body interaction. A variety of psychological mechanisms, such as expectation, conditioning, anxiety modulation, and reward, have been identified, and a number of neurochemical networks have been characterized across different conditions, such as pain and motor disorders. What has emerged from the recent insights into the neurobiology of placebo and nocebo effects is that the psychosocial context around the patient and the therapy, which represents the ritual of the therapeutic act, may change the biochemistry and the neuronal circuitry of the patient's brain. Furthermore, the mechanisms activated by placebos and nocebos have been found to be the same as those activated by drugs, which suggests a cognitive/affective interference with drug action. Overall, these findings highlight the important role of therapeutic rituals in the overall therapeutic outcome, including hypnosis, which may have profound implications both in routine medical practice and in the clinical trials setting.
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Facing the experience of pain: A neuropsychological perspective. Phys Life Rev 2014; 11:540-52. [DOI: 10.1016/j.plrev.2013.12.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Accepted: 12/17/2013] [Indexed: 01/09/2023]
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Bérubé P, Poulin JF, Laforest S, Drolet G. Enkephalin knockdown in the basolateral amygdala reproduces vulnerable anxiety-like responses to chronic unpredictable stress. Neuropsychopharmacology 2014; 39:1159-68. [PMID: 24213354 PMCID: PMC3957109 DOI: 10.1038/npp.2013.316] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 10/16/2013] [Accepted: 10/18/2013] [Indexed: 12/29/2022]
Abstract
The endogenous enkephalins (ENKs) are potential candidates participating in the naturally occurring variations in coping styles and determining the individual capacities for adaptation during chronic stress exposure. Here we demonstrate that there is a large variance in individual behavioral, as well as in physiological outcomes, in a population of Sprague-Dawley rats subjected to 3 weeks of chronic unpredictable stress (CUS). Separation of resilient and vulnerable subpopulations reveals specific long-term neuroadaptation in the ENKergic brain circuits. ENK mRNA expression was greatly reduced in the posterior basolateral nucleus of amygdala (BLAp) in vulnerable individuals. In contrast, ENK mRNA levels were similar in resilient and control (unstressed) individuals. Another group of rats were used for lentiviral-mediated knockdown of ENK to assess whether a decrease of ENK expression in the BLAp reproduces the behavioral disturbances found in vulnerable individuals. ENK knockdown specifically located in the BLAp was sufficient to increase anxiety in the behavioral tests, such as social interaction and elevated plus maze when compared with control individuals. These results show that specific neuroadaptation mediated by the ENKergic neurotransmission in the BLAp is a key regulator of resilience, whereas a decrease of the ENK in the BLAp is a maladaptation mechanism, which mediates the behavioral dichotomy observed between vulnerable and resilient following 3 weeks of CUS.
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Affiliation(s)
- Patrick Bérubé
- Centre de recherche du CHU de Québec, Axe Neurosciences, Université Laval, Quebec, QC, Canada
| | - Jean-François Poulin
- Centre de recherche du CHU de Québec, Axe Neurosciences, Université Laval, Quebec, QC, Canada
| | - Sylvie Laforest
- Centre de recherche du CHU de Québec, Axe Neurosciences, Université Laval, Quebec, QC, Canada
| | - Guy Drolet
- Centre de recherche du CHU de Québec, Axe Neurosciences, Université Laval, Quebec, QC, Canada,Centre de recherche du CHU de Québec, Axe Neurosciences, Université Laval, CHUL P-09800, 2705 Laurier, Québec, QC, Canada G1V 4G2. Tel: +418 525 4444, ext. 47979, Fax: +418 654 2753, E-mail:
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Benedetti F, Amanzio M. Mechanisms of the placebo response. Pulm Pharmacol Ther 2013; 26:520-3. [DOI: 10.1016/j.pupt.2013.01.006] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2012] [Accepted: 01/14/2013] [Indexed: 12/19/2022]
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Bérubé P, Laforest S, Bhatnagar S, Drolet G. Enkephalin and dynorphin mRNA expression are associated with resilience or vulnerability to chronic social defeat stress. Physiol Behav 2013; 122:237-45. [PMID: 23665402 DOI: 10.1016/j.physbeh.2013.04.009] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2012] [Revised: 04/09/2013] [Accepted: 04/29/2013] [Indexed: 12/12/2022]
Abstract
There are important and enduring differences between individuals in the magnitude of all aspects of the stress response. Among the neuropeptide systems, the endogenous opioids enkephalin (ENK) and dynorphin (DYN), are very interesting candidates to participate in the naturally occurring variations in coping styles and to determine the individual capacity for adaptation during chronic stress exposure. Under chronic social stress exposure, we hypothesize that changes in the ENKergic vs DYNergic neuronal systems within specific nuclei of the basal forebrain contribute to naturally occurring variations in coping styles and will determine individual capacities for stress adaptation. Sprague-Dawley rats were exposed to a resident-intruder model of defeat for 7 days. The average latency to be defeated over seven consecutive days was calculated for each intruder rat. Based on this distribution, we chose an average defeat latency of 350s as a cutoff criterion to define resilient and vulnerable rats. A subpopulation assumed a subordinate posture in a relatively short latency (<350s, SL) and the other subpopulation resisted defeat resulting in longer latencies (>350s, LL) to assume this posture and were identified as being vulnerable and resilient respectively. Rats were euthanized 24h after the last stress session. ENK mRNA expression was lower in the basolateral nucleus of the amygdala in vulnerable compared to control and resilient individuals. In contrast, there was no difference between resilient and control individuals. DYN mRNA is increased only within the dorsal and medial shell of the NAc of vulnerable rats compared to control individuals. There was no difference between resilient and control individuals. DYN mRNA is increased in resilient individuals in the central area of the striatum, caudal part, compared to control individuals. DYN is also increased in medial area of the striatum, caudal part in resilient and vulnerable compared to control individuals. These results have broad implications for understanding the functional roles of opioid neurotransmission following repeated social stress and suggest that ENK could facilitate the adaptation of behavioral responses by opposition to the DYN neurotransmission that appears to promote maladaptive behavioral response to chronic social stress.
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Affiliation(s)
- Patrick Bérubé
- Centre de recherche du CHU de Québec (CHUL), Axe Neurosciences, Université Laval, Québec, QC, Canada.
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Wen D, Zang G, Sun D, Yang S, Yu F, Li S, Ma C, Cong B. Effects of CCK-8 on the reinstatement of morphine-induced CPP and expression of behavioral sensitization in rats. Neuroscience 2013; 238:230-41. [DOI: 10.1016/j.neuroscience.2013.02.057] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Revised: 02/20/2013] [Accepted: 02/21/2013] [Indexed: 10/27/2022]
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Ito T, Igarashi H, Uehara H, Berna MJ, Jensen RT. Causes of death and prognostic factors in multiple endocrine neoplasia type 1: a prospective study: comparison of 106 MEN1/Zollinger-Ellison syndrome patients with 1613 literature MEN1 patients with or without pancreatic endocrine tumors. Medicine (Baltimore) 2013; 92:135-181. [PMID: 23645327 PMCID: PMC3727638 DOI: 10.1097/md.0b013e3182954af1] [Citation(s) in RCA: 138] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Multiple endocrine neoplasia type 1 (MEN1) is classically characterized by the development of functional or nonfunctional hyperplasia or tumors in endocrine tissues (parathyroid, pancreas, pituitary, adrenal). Because effective treatments have been developed for the hormone excess state, which was a major cause of death in these patients in the past, coupled with the recognition that nonendocrine tumors increasingly develop late in the disease course, the natural history of the disease has changed. An understanding of the current causes of death is important to tailor treatment for these patients and to help identify prognostic factors; however, it is generally lacking.To add to our understanding, we conducted a detailed analysis of the causes of death and prognostic factors from a prospective long-term National Institutes of Health (NIH) study of 106 MEN1 patients with pancreatic endocrine tumors with Zollinger-Ellison syndrome (MEN1/ZES patients) and compared our results to those from the pooled literature data of 227 patients with MEN1 with pancreatic endocrine tumors (MEN1/PET patients) reported in case reports or small series, and to 1386 patients reported in large MEN1 literature series. In the NIH series over a mean follow-up of 24.5 years, 24 (23%) patients died (14 MEN1-related and 10 non-MEN1-related deaths). Comparing the causes of death with the results from the 227 patients in the pooled literature series, we found that no patients died of acute complications due to acid hypersecretion, and 8%-14% died of other hormone excess causes, which is similar to the results in 10 large MEN1 literature series published since 1995. In the 2 series (the NIH and pooled literature series), two-thirds of patients died from an MEN1-related cause and one-third from a non-MEN1-related cause, which agrees with the mean values reported in 10 large MEN1 series in the literature, although in the literature the causes of death varied widely. In the NIH and pooled literature series, the main causes of MEN1-related deaths were due to the malignant nature of the PETs, followed by the malignant nature of thymic carcinoid tumors. These results differ from the results of a number of the literature series, especially those reported before the 1990s. The causes of non-MEN1-related death for the 2 series, in decreasing frequency, were cardiovascular disease, other nonendocrine tumors > lung diseases, cerebrovascular diseases. The most frequent non-MEN1-related tumor deaths were colorectal, renal > lung > breast, oropharyngeal. Although both overall and disease-related survival are better than in the past (30-yr survival of NIH series: 82% overall, 88% disease-related), the mean age at death was 55 years, which is younger than expected for the general population.Detailed analysis of causes of death correlated with clinical, laboratory, and tumor characteristics of patients in the 2 series allowed identification of a number of prognostic factors. Poor prognostic factors included higher fasting gastrin levels, presence of other functional hormonal syndromes, need for >3 parathyroidectomies, presence of liver metastases or distant metastases, aggressive PET growth, large PETs, or the development of new lesions.The results of this study have helped define the causes of death of MEN1 patients at present, and have enabled us to identify a number of prognostic factors that should be helpful in tailoring treatment for these patients for both short- and long-term management, as well as in directing research efforts to better define the natural history of the disease and the most important factors determining long-term survival at present.
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Affiliation(s)
- Tetsuhide Ito
- From the Department of Medicine and Bioregulatory Science (TI, HI), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Digestive Diseases Branch (TI, HI, HU, MJB, RTJ), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; and Hôpital Kirchberg (MJB), Luxembourg, Luxembourg
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Volkow ND, Wang GJ, Tomasi D, Baler RD. Obesity and addiction: neurobiological overlaps. Obes Rev 2013; 14:2-18. [PMID: 23016694 PMCID: PMC4827343 DOI: 10.1111/j.1467-789x.2012.01031.x] [Citation(s) in RCA: 513] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2012] [Revised: 08/10/2012] [Accepted: 08/10/2012] [Indexed: 12/14/2022]
Abstract
Drug addiction and obesity appear to share several properties. Both can be defined as disorders in which the saliency of a specific type of reward (food or drug) becomes exaggerated relative to, and at the expense of others rewards. Both drugs and food have powerful reinforcing effects, which are in part mediated by abrupt dopamine increases in the brain reward centres. The abrupt dopamine increases, in vulnerable individuals, can override the brain's homeostatic control mechanisms. These parallels have generated interest in understanding the shared vulnerabilities between addiction and obesity. Predictably, they also engendered a heated debate. Specifically, brain imaging studies are beginning to uncover common features between these two conditions and delineate some of the overlapping brain circuits whose dysfunctions may underlie the observed deficits. The combined results suggest that both obese and drug-addicted individuals suffer from impairments in dopaminergic pathways that regulate neuronal systems associated not only with reward sensitivity and incentive motivation, but also with conditioning, self-control, stress reactivity and interoceptive awareness. In parallel, studies are also delineating differences between them that centre on the key role that peripheral signals involved with homeostatic control exert on food intake. Here, we focus on the shared neurobiological substrates of obesity and addiction.
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Affiliation(s)
- N D Volkow
- National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland 20892, USA.
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Effects of exogenous cholecystokinin octapeptide on acquisition of naloxone precipitated withdrawal induced conditioned place aversion in rats. PLoS One 2012; 7:e41860. [PMID: 22848639 PMCID: PMC3407117 DOI: 10.1371/journal.pone.0041860] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2012] [Accepted: 06/26/2012] [Indexed: 11/22/2022] Open
Abstract
Cholecystokinin octapeptide (CCK-8), a gut-brain peptide, regulates a variety of physiological behavioral processes. Previously, we reported that exogenous CCK-8 attenuated morphine-induced conditioned place preference, but the possible effects of CCK-8 on aversively motivated drug seeking remained unclear. To investigate the effects of endogenous and exogenous CCK on negative components of morphine withdrawal, we evaluated the effects of CCK receptor antagonists and CCK-8 on the naloxone-precipitated withdrawal-induced conditioned place aversion (CPA). The results showed that CCK2 receptor antagonist (LY-288,513, 10 µg, i.c.v.), but not CCK1 receptor antagonist (L-364,718, 10 µg, i.c.v.), inhibited the acquisition of CPA when given prior to naloxone (0.3 mg/kg) administration in morphine-dependent rats. Similarly, CCK-8 (0.1–1 µg, i.c.v.) significantly attenuated naloxone-precipitated withdrawal-induced CPA, and this inhibitory function was blocked by co-injection with L-364,718. Microinjection of L-364,718, LY-288,513 or CCK-8 to saline pretreated rats produced neither a conditioned preference nor aversion, and the induction of CPA by CCK-8 itself after morphine pretreatments was not significant. Our study identifies a different role of CCK1 and CCK2 receptors in negative affective components of morphine abstinence and an inhibitory effect of exogenous CCK-8 on naloxone-precipitated withdrawal-induced CPA via CCK1 receptor.
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Seehuus B, Blokhuis H, Mendl M, Keeling L. Developing a method to investigate motivational sequences in the chick. ACTA AGR SCAND A-AN 2012. [DOI: 10.1080/09064702.2012.721388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Del Boca C, Lutz PE, Le Merrer J, Koebel P, Kieffer BL. Cholecystokinin knock-down in the basolateral amygdala has anxiolytic and antidepressant-like effects in mice. Neuroscience 2012; 218:185-95. [PMID: 22613736 DOI: 10.1016/j.neuroscience.2012.05.022] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2012] [Revised: 04/06/2012] [Accepted: 05/08/2012] [Indexed: 10/28/2022]
Abstract
Cholecystokinin (CCK) is a neuropeptide widely distributed in the mammalian brain. This peptide regulates many physiological functions and behaviors, such as cardio-respiratory control, thermoregulation, nociception, feeding, memory processes and motivational responses, and plays a prominent role in emotional responses including anxiety and depression. CCK-expressing brain regions involved in these functions remain unclear and their identification represents an important step towards understanding CCK function in the brain. The basolateral amygdala (BLA) is strongly involved in emotional processing and expresses high levels of CCK. In this study we examined the contribution of CCK expressed in this brain region to emotional responses in mice. To knockdown CCK specifically in the BLA, we used stereotaxic delivery of recombinant adeno-associated viral vectors expressing a CCK-targeted shRNA. This procedure efficiently reduced CCK levels locally. shCCK-treated animals showed reduced levels of anxiety in the elevated plus-maze, and lower despair-like behavior in the forced swim test. Our data demonstrate that CCK expressed in the BLA represents a key brain substrate for anxiogenic and depressant effects of the peptide. The study also suggests that elevated amygdalar CCK could contribute to panic and major depressive disorders that have been associated with CCK dysfunction in humans.
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Affiliation(s)
- C Del Boca
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université de Strasbourg, Illkirch-Graffenstaden, France
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Cignacco E, Hamers JPH, Stoffel L, van Lingen RA, Gessler P, McDougall J, Nelle M. The efficacy of non-pharmacological interventions in the management of procedural pain in preterm and term neonates. Eur J Pain 2012; 11:139-52. [PMID: 16580851 DOI: 10.1016/j.ejpain.2006.02.010] [Citation(s) in RCA: 176] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2005] [Revised: 02/04/2006] [Accepted: 02/19/2006] [Indexed: 11/28/2022]
Abstract
BACKGROUND Neonates in a neonatal intensive care unit are exposed to a high number of painful procedures. Since repeated and sustained pain can have consequences for the neurological and behaviour-oriented development of the newborn, the greatest attention needs to be paid to systematic pain management in neonatology. Non-pharmacological treatment methods are being increasingly discussed with regard to pain prevention and relief either alone or in combination with pharmacological treatment. AIMS To identify effective non-pharmacological interventions with regard to procedural pain in neonates. METHODS A literature search was conducted via the MedLine, CINAHL, Cochrane Library databases and complemented by a handsearch. The literature search covered the period from 1984 to 2004. Data were extracted according to pre-defined criteria by two independent reviewers and methodological quality was assessed. RESULTS 13 randomised controlled studies and two meta-analyses were taken into consideration with regard to the question of current nursing practice of non-pharmacological pain management methods. The selected interventions were "non-nutritive sucking", "music", "swaddling", "positioning", "olfactory and multisensorial stimulation", "kangaroo care" and "maternal touch". There is evidence that the methods of "non-nutritive sucking", "swaddling" and "facilitated tucking" do have a pain-alleviating effect on neonates. CONCLUSIONS Some of the non-pharmacological interventions have an evident favourable effect on pulse rate, respiration and oxygen saturation, on the reduction of motor activity, and on the excitation states after invasive measures. However, unambiguous evidence of this still remains to be presented. Further research should emphasise the use of validated pain assessment instruments for the evaluation of the pain-alleviating effect of non-pharmacological interventions.
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Affiliation(s)
- Eva Cignacco
- Department for Obstetrics and Neonatology, Women's and Children's Clinic, University Hospital Insel, Bern, Effingerstr. 102, CH-3010 Bern, Switzerland.
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Wen D, Cong B, Ma C, Yang S, Yu H, Ni Z, Li S. The effects of exogenous CCK-8 on the acquisition and expression of morphine-induced CPP. Neurosci Lett 2012; 510:24-8. [PMID: 22245440 DOI: 10.1016/j.neulet.2011.12.063] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2011] [Revised: 11/17/2011] [Accepted: 12/29/2011] [Indexed: 11/27/2022]
Abstract
Cholecystokinin octapeptide (CCK-8) is the most potent endogenous anti-opioid peptide and regulates a variety of physiological processes. In our previous study, we found that exogenous CCK-8 attenuated naloxone-induced withdrawal symptoms, but the possible regulative effects of CCK-8 on the rewarding effects of morphine were not examined. In the present study, we aimed to determine the exact effects of exogenous CCK-8 at various doses on the rewarding action of morphine by utilizing the unbiased conditioned place preference (CPP) paradigm. We therefore examined the effects of CCK-8 on the acquisition, expression and extinction of morphine-induced CPP and on locomotor activity. The results showed that CCK-8 (0.01-1μg, i.c.v.), administered alone, induced neither CPP nor place aversion, but blocked the acquisition of CPP when administered with 10mg/kg morphine. The highest dose of CCK-8 (1μg) administered before CPP testing increased CPP and, along with lower doses (0.1μg), reduced its extinction. In addition, the highest dose (1μg) of CCK-8 suppressed locomotor activity. Our study provides the first behavioral evidence for the inhibitory effects of exogenous CCK-8 on rewarding activity and reveals significant effects of exogenous CCK-8 on various stages of place preference and the development of opioid dependence.
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Affiliation(s)
- Di Wen
- Department of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Shijiazhuang 050017, PR China
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Abstract
The opioid system plays a crucial role in the neural modulation of anxiety. The involvement of opioid ligands and receptors in physiological and dysfunctional forms of anxiety is supported by findings from a wide range of preclinical and clinical studies, including clinical trials, experimental research, and neuroimaging, genetic, and epidemiological data. In this review we provide a summary of studies from a variety of research disciplines to elucidate the role of the opioid system in the neurobiology of anxiety. First, we report data from preclinical studies using animal models to examine the modulatory role of central opioid system on defensive responses conducive to fear and anxiety. Second, we summarize the human literature providing evidence that clinical and experimental human studies are consistent with preclinical models. The implication of these data is that activation of the opioid system leads to anxiolytic responses both in healthy subjects and in patients suffering from anxiety disorders. The role of opioids in suppressing anxiety may serve as an adaptive mechanism, collocated in the general framework of opioid neurotransmission blunting acute negative and distressing affective responses.
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Affiliation(s)
- A Colasanti
- Neuropsychopharmacology Unit, Centre for Pharmacology and Therapeutics, Division of Experimental Medicine, Imperial College London, London, UK.
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46
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Pollo A, Carlino E, Benedetti F. Placebo mechanisms across different conditions: from the clinical setting to physical performance. Philos Trans R Soc Lond B Biol Sci 2011; 366:1790-8. [PMID: 21576136 DOI: 10.1098/rstb.2010.0381] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Although the great increase in interest in the placebo phenomenon was spurred by the clinical implications of its use, the progressive elucidation of the neurobiological and pharmacological mechanisms underlying the placebo effect also helps cast new light on the relationship between mind (and brain) and body, a topic of foremost philosophical importance but also a major medical issue in light of the complex interactions between the brain on the one hand and body functions on the other. While the concept of placebo can be a general one, with a broad definition generally applicable to many different contexts, the description of the cerebral processes called into action in specific situations can vary widely. In this paper, examples will be given where physiological or pathological conditions are altered following the administration of an inert substance or verbal instructions tailored to induce expectation of a change, and explanations will be offered with details on neurotransmitter changes and neural pathways activated. As an instance of how placebo effects can extend beyond the clinical setting, data in the physical performance domain and implications for sport competitions will also be presented and discussed.
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Affiliation(s)
- Antonella Pollo
- Department of Neuroscience, University of Turin, and National Institute of Neuroscience, Turin, Italy
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Knudsen L, Petersen GL, Nørskov KN, Vase L, Finnerup N, Jensen TS, Svensson P. Review of neuroimaging studies related to pain modulation. Scand J Pain 2011; 2:108-120. [DOI: 10.1016/j.sjpain.2011.05.005] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2010] [Accepted: 05/18/2011] [Indexed: 12/28/2022]
Abstract
Abstract
Background and purpose: A noxious stimulus does not necessarily cause pain. Nociceptive signals arising from a noxious stimulus are subject to modulation via endogenous inhibitory and facilitatory mechanisms as they travel from the periphery to the dorsal horn or brainstem and on to higher brain sites. Research on the neural structures underlying endogenous pain modulation has largely been restricted to animal research due to the invasiveness of such studies (e.g., spinal cord transection, brain lesioning, brain site stimulation). Neuroimaging techniques (e.g., magnetoencephalography (MEG), positron emission tomography (PET) and functional magnetic resonance imaging (fMRI)) provide non-invasive means to study neural structures in humans. The aim is to provide a narrative review of neuroimaging studies related to human pain control mechanisms.
Methods: The approach taken is to summarise specific pain modulation mechanisms within the somatosensory (diffuse noxious inhibitory controls, acupuncture, movement), affective (depression, anxiety, catastrophizing, stress) and cognitive (anticipation/placebo, attention/distraction, hypnosis)domains with emphasis on the contribution of neuroimaging studies.
Results and conclusions: Findings from imaging studies are complex reflecting activation or deactivation in numerous brain areas. Despite this, neuroimaging techniques have clarified supraspinal sites involved in a number of pain control mechanisms. The periaqueductal grey (PAG) is one area that has consistently been shown to be activated across the majority of pain mechanisms. Activity in the rostral ventromedial medulla known to relay descending modulation from the PAG, has also been observed both during acupuncture analgesia and anxiety-induced hyperalgesia. Other brain areas that appear to be involved in a number of mechanisms are the anterior cingulate cortex, prefrontal cortex, orbitofrontal cortex and nucleus accumbens, but their exact role is less clear.
Implications: Neuroimaging studies have provided essential information about the pain modulatory pathways under normal conditions, but much is still to be determined. Understanding the mechanisms of pain control is important for understanding the mechanisms that contribute to failed pain control in chronic pain. Applying fMRI outside the brain, such as in the trigeminal nucleus caudalis of the spinotrigeminal pathway and in the dorsal horn of the spinal cord, and coupling brain activity with activity at these sites may help improve our understanding of the function of brain sites and shed light on functional connectivity in the pain pathway.
© 2011 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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Affiliation(s)
- Lone Knudsen
- Danish Pain Research Center , Aarhus University Hospital Nørrebrogade 44, Building 1A , 8000 Aarhus C , Denmark
| | - Gitte Laue Petersen
- School of Psychology , Aarhus University, Jens Chr. Skous Vej 4 , 8000 Aarhus C , Denmark
| | | | - Lene Vase
- School of Psychology , Aarhus University, Jens Chr. Skous Vej 4 , 8000 Aarhus C , Denmark
| | - Nanna Finnerup
- Danish Pain Research Center , Aarhus University Hospital Nørrebrogade 44, Building 1A , 8000 Aarhus C , Denmark
- Center for Functionally Integrative Neuroscience, MindLab , Aarhus University Hospital, Nørrebrogade 44, Building 10G , 8000 Aarhus C , Denmark
| | - Troels Staehelin Jensen
- Danish Pain Research Center , Aarhus University Hospital Nørrebrogade 44, Building 1A , 8000 Aarhus C , Denmark
- Center for Functionally Integrative Neuroscience, MindLab , Aarhus University Hospital, Nørrebrogade 44, Building 10G , 8000 Aarhus C , Denmark
| | - Peter Svensson
- Center for Functionally Integrative Neuroscience, MindLab , Aarhus University Hospital, Nørrebrogade 44, Building 10G , 8000 Aarhus C , Denmark
- Department of Clinical Oral Physiology, School of Dentistry , Aarhus University, Vennelyst Boulevard 9 , 8000 Aarhus C , Denmark
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Bingel U, Wanigasekera V, Wiech K, Ni Mhuircheartaigh R, Lee MC, Ploner M, Tracey I. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci Transl Med 2011; 3:70ra14. [PMID: 21325618 DOI: 10.1126/scitranslmed.3001244] [Citation(s) in RCA: 492] [Impact Index Per Article: 35.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Evidence from behavioral and self-reported data suggests that the patients' beliefs and expectations can shape both therapeutic and adverse effects of any given drug. We investigated how divergent expectancies alter the analgesic efficacy of a potent opioid in healthy volunteers by using brain imaging. The effect of a fixed concentration of the μ-opioid agonist remifentanil on constant heat pain was assessed under three experimental conditions using a within-subject design: with no expectation of analgesia, with expectancy of a positive analgesic effect, and with negative expectancy of analgesia (that is, expectation of hyperalgesia or exacerbation of pain). We used functional magnetic resonance imaging to record brain activity to corroborate the effects of expectations on the analgesic efficacy of the opioid and to elucidate the underlying neural mechanisms. Positive treatment expectancy substantially enhanced (doubled) the analgesic benefit of remifentanil. In contrast, negative treatment expectancy abolished remifentanil analgesia. These subjective effects were substantiated by significant changes in the neural activity in brain regions involved with the coding of pain intensity. The positive expectancy effects were associated with activity in the endogenous pain modulatory system, and the negative expectancy effects with activity in the hippocampus. On the basis of subjective and objective evidence, we contend that an individual's expectation of a drug's effect critically influences its therapeutic efficacy and that regulatory brain mechanisms differ as a function of expectancy. We propose that it may be necessary to integrate patients' beliefs and expectations into drug treatment regimes alongside traditional considerations in order to optimize treatment outcomes.
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Affiliation(s)
- Ulrike Bingel
- Oxford Centre for Functional MRI of the Brain, Nuffield Department of Clinical Neurosciences (Division of Anaesthetics), University of Oxford, OX3 9DU Oxford, UK.
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Salomé N, Taube M, Egecioglu E, Hansson C, Stenström B, Chen D, Andersson DR, Georg Kuhn H, Ohlsson C, Dickson SL. Gastrectomy alters emotional reactivity in rats: neurobiological mechanisms. Eur J Neurosci 2011; 33:1685-95. [PMID: 21535247 PMCID: PMC3110309 DOI: 10.1111/j.1460-9568.2011.07640.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Gastrectomy (Gsx) is associated with altered emotional function and a predisposition to depression/anxiety disorders. Here we investigated the effects of Gsx on emotional reactivity in rats and explored the underlying neurobiological mechanisms. Gsx- and sham-operated rats were exposed to behavioural tests that explore anxiety- and depression-like behaviour (open field, black and white box, elevated plus maze, social interaction, forced swim) as well as memory (object recognition). The potential neurobiological mechanisms underlying these differences were explored by measuring (i) turnover of candidate neurotransmitter systems in the nucleus accumbens, (ii) hippocampal neurogenesis by BrdU labelling or by analysis of candidate genes involved in neuronal growth and (iii) changes in mRNA expression of candidate genes in dissected hippocampal and amygdala tissue. Data from individual behavioural tests as well as from multivariate analysis revealed differing emotional reactivity between Gsx- and sham-operated rats. Gsx rats showed reduced emotional reactivity in a new environment and decreased depression-like behaviour. Accumbal serotonin and dopamine turnover were both reduced in Gsx rats. Gsx also led to a memory deficit, although hippocampal neurogenesis was unaffected. Of the many candidate genes studied by real-time RT-PCR, we highlight a Gsx-associated decrease in expression of Egr-1, a transcription factor linked to neural plasticity and cognition, in the hippocampus and amygdala. Thus, Gsx induces an alteration of emotional reactivity and a memory/cognitive deficit that is associated with reduced turnover of serotonin and dopamine in the nucleus accumbens and decreased expression of Egr-1 in the hippocampus and amygdala.
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Affiliation(s)
- Nicolas Salomé
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Medicinaregatan 11, SE-40530 Gothenburg, Sweden
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50
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Lovell PV, Mello CV. Brain expression and song regulation of the cholecystokinin gene in the zebra finch (Taeniopygia guttata). J Comp Neurol 2011; 519:211-37. [PMID: 21165972 DOI: 10.1002/cne.22513] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The gene encoding cholecystokinin (Cck) is abundantly expressed in the mammalian brain and has been associated with such functions as feeding termination and satiety, locomotion and self-stimulation, the modulation of anxiety-like behaviors, and learning and memory. Here we describe the brain expression and song regulation of Cck in the brain of the adult male zebra finch (Taeniopygia guttata), a songbird species. Using in situ hybridization we demonstrate that Cck is highly expressed in several discrete brain regions, most prominently the caudalmost portion of the hippocampal formation, the caudodorsal nidopallial shelf and the caudomedial nidopallium (NCM), the core or shell regions of dorsal thalamic nuclei, dopaminergic cell groups in the mesencephalon and pons, the principal nucleus of the trigeminal nerve, and the dorsal raphe. Cck was largely absent in song control system, a group of nuclei required for vocal learning and song production in songbirds, although sparse labeling was detected throughout the striatum, including song nucleus area X. We also show that levels of Cck mRNA and the number of labeled cells increase in the NCM of males and females following auditory stimulation with conspecific song. Double labeling further reveals that the majority of Cck cells, excluding those in the reticular nucleus of the thalamus, are non-GABAergic. Together, these data provide the first comprehensive characterization of Cck expression in a songbird, and suggest a possible involvement of Cck regulation in important aspects of birdsong biology, such as perceptual processing, auditory memorization, and/or vocal-motor control of song production.
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Affiliation(s)
- Peter V Lovell
- Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR 97239, USA
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