• Brain plasticity
• Focal neuropathy
• Neuropathic algesia
• Phytochemicals
• Polyneuropathy

• Humans
• Diabetic Neuropathies/etiology
• Diabetic Neuropathies/metabolism
• Diabetic Neuropathies/pathology
• Diabetic Neuropathies/physiopathology
• Diabetic Neuropathies/drug therapy
• Neuralgia/etiology
• Quality of Life
• Diabetes Mellitus
• Animals

• Diabetes
• Glutamate
• Insulin release
• Metabotropic glutamate receptors
• Neuroprotection
• Pancreatic β-cells
• Peripheral neuropathy

• Humans
• Animals
• Diabetic Neuropathies/metabolism
• Diabetic Neuropathies/drug therapy
• Insulin/metabolism
• Receptors, Metabotropic Glutamate/metabolism
• Insulin Secretion/drug effects
• Glutamic Acid/metabolism
• Receptors, Glutamate/metabolism

• BDNF
• GABAA receptor
• NMDA receptor
• Opioid receptors
• Trigeminal neuropathic pain

• Diabetes
• Hyperglycemia
• Neuropathy
• Phototherapy
• Streptozotocin
• Western blot

• Anterior cingulate cortex
• Cancer pain
• Deep brain stimulation
• Inflammatory pain
• Neuropathic pain
• Pathological pain
• Transcranial direct current stimulation
• Transcranial magnetic stimulation

• Animals
• Gyrus Cinguli
• Humans
• Neuralgia
• Pain Management
• Translational Research, Biomedical

The anterior cingulate cortex is a limbic region associated with the emotional processing of pain. How neuropathic and inflammatory pain models alter the neurophysiology of specific subsets of neurons in the anterior cingulate cortex remains incompletely understood. Here, we used a GRM2^Cre:tdtomato reporter mouse line to identify a population of pyramidal neurons selectively localized to layer II/III of the murine anterior cingulate cortex. GRM2encodes the group II metabotropic glutamate receptor subtype 2 which possesses analgesic properties in mouse and human models, although its function in the anterior cingulate cortex is not known. The majority of GRM2-tdtomato anterior cingulate cortex neurons expressed GRM2gene product in situ but did not overlap with cortical markers of local inhibitory interneurons, parvalbumin or somatostatin. Physiological properties of GRM2-tdtomato anterior cingulate cortex neurons were investigated using whole-cell patch clamp techniques in slice from animals with neuropathic or inflammatory pain, and controls. After hind-paw injection of Complete Freund’s Adjuvant or chronic constriction injury, GRM2-tdtomato anterior cingulate cortex neurons exhibited enhanced excitability as measured by an increase in the number of evoked action potentials and a decreased rheobase. This hyperexcitability was reversed pharmacologically by bath application of the metabotropic glutamate receptor subtype 2 agonist (2R, 4R)-4-Aminopyrrolidine-2,4-dicarboxylate APDC (1 µM) in both inflammatory and neuropathic models. We conclude that layer II/III pyramidal GRM2-tdtomato anterior cingulate cortex neurons express functional group II metabotropic glutamate receptors and undergo changes to membrane biophysical properties under conditions of inflammatory and neuropathic pain.

• Anterior cingulate cortex
• group II
• inflammatory
• metabotropic glutamate receptor
• neuropathic
• pain

• Diabetes
• amacrine cell
• inhibition
• retina

Pain is comprised of both sensory and affective components. The anterior cingulate cortex (ACC) is a key brain region involved in the emotional processing of pain. Specifically, glutamatergic transmission within the ACC has been shown to modulate pain-related aversion. In the present study, we use in vivo optogenetics to activate or silence, using channelrhodopsin (ChR2) and archaerhodopsin (ArchT) respectively, calmodulin-kinase IIα (CaMKIIα)-expressing excitatory glutamatergic neurons of the ACC during a formalin-induced conditioned place aversion (F-CPA) behavioral paradigm in both female and male adult Sprague-Dawley rats. Expression of c-Fos, a marker of neuronal activity, was assessed within the ACC using immunohistochemistry. Optogenetic inhibition of glutamatergic neurons of the ACC abolished F-CPA without affecting formalin-induced nociceptive behavior during conditioning. In male rats, optogenetic activation of ACC glutamatergic neurons decreased formalin-induced nociceptive behavior during conditioning without affecting F-CPA. Interestingly, the opposite effect was seen in females, where optogenetic activation of glutamatergic neurons of the ACC increased formalin-induced nociceptive behavior during conditioning. The abolition of F-CPA following optogenetic inhibition of glutamatergic neurons of the ACC was associated with a reduction in c-Fos immunoreactivity in the ACC in male rats, but not female rats. These results suggest that excitatory glutamatergic neurons of the ACC play differential and sex-dependent roles in the aversion learning and acute sensory components of pain.

• anterior cingulate cortex
• c-Fos
• conditioned place aversion
• formalin
• glutamate neurons
• inflammatory pain
• optogenetics
• rat

• ACC
• Adenylyl cyclase subtype 1
• Chronic pain
• Long-term potentiation
• NB001

• Adenosine Triphosphate/administration & dosage
• Adenosine Triphosphate/analogs & derivatives
• Adenosine Triphosphate/metabolism
• Adenylyl Cyclase Inhibitors/administration & dosage
• Adenylyl Cyclase Inhibitors/metabolism
• Adenylyl Cyclases/metabolism
• Analgesics/administration & dosage
• Analgesics/metabolism
• Animals
• Chronic Pain/drug therapy
• Chronic Pain/metabolism
• Drug Delivery Systems/methods
• Humans
• Long-Term Potentiation/drug effects
• Long-Term Potentiation/physiology
• Neuronal Plasticity/drug effects
• Neuronal Plasticity/physiology
• Neurons/drug effects
• Neurons/metabolism

Electroacupuncture (EA) is reported effective in alleviating pain-related emotion; however, the underlying mechanism of its effects still needs to be elucidated. The NPS-NPSR system has been validated for the involvement in the modulation of analgesia and emotional behavior. Here, we aimed to investigate the role of the NPS-NPSR system in the anterior cingulate cortex (ACC), hypothalamus, and central amygdala (CeA) in the use of EA to relieve affective pain modeled by complete Freund's adjuvant- (CFA-) evoked conditioned place aversion (C-CPA). Materials and Methods. CFA injection combined with a CPA paradigm was introduced to establish the C-CPA model, and the elevated O-maze (EOM) was used to test the behavioral changes after model establishment. We further explored the expression of NPS and NPSR at the protein and gene levels in the brain regions of interest by immunofluorescence staining and quantitative real-time PCR.

We observed that EA stimulation delivered to the bilateral Zusanli (ST36) and Kunlun (BL60) acupoints remarkably inhibited sensory pain, pain-evoked place aversion, and anxiety-like behavior. The current study showed that EA significantly enhanced the protein expression of this peptide system in the ACC and hypothalamus, while the elevated expression of NPSR protein alone was just confined to the affected side in the CeA. Moreover, EA remarkably upregulated the mRNA expression of NPS in CeA, ACC, and hypothalamus and NPSR mRNA in the hypothalamus and CeA.

These data suggest the effectiveness of EA in alleviating affective pain, and these benefits may at least partially be attributable to the upregulation of the NPS-NPSR system in the ACC and hypothalamus.

To find satisfactory treatment strategies for neuropathic pain syndromes, the cellular mechanisms should be illuminated. Central sensitization is a generator of pain hypersensitivity, and is mainly reflected in neuronal hyperexcitability in pain pathway. Neuronal excitability depends on two components, the synaptic inputs and the intrinsic excitability. Previous studies have focused on the synaptic plasticity in different forms of pain. But little is known about the changes of neuronal intrinsic excitability in neuropathic pain. To address this question, whole-cell patch clamp recordings were performed to study the synaptic transmission and neuronal intrinsic excitability 1 week after spared nerve injury (SNI) or sham operation in male C57BL/6J mice. We found increased spontaneous excitatory postsynaptic currents (sEPSC) frequency in layer II/III pyramidal neurons of anterior cingulate cortex (ACC) from mice with neuropathic pain. Elevated intrinsic excitability of these neurons after nerve injury was also picked up, which was reflected in gain of input-output curve, inter-spike interval (ISI), spike threshold and Refractory period (RP). Besides firing rate related to neuronal intrinsic excitability, spike timing also plays an important role in neural information processing. The precision of spike timing measured by standard deviation of spike timing (SDST) was decreased in neuropathic pain state. The electrophysiological studies revealed the elevated intrinsic excitation in layer II/III pyramidal neurons of ACC in mice with neuropathic pain, which might contribute to central excitation.

• anterior cingulate cortex
• intrinsic excitability
• neuropathic pain
• refractory period
• spike threshold
• spontaneous excitatory postsynaptic currents

PKMζ is a persistently active PKC isoform proposed to maintain late-LTP and long-term memory. But late-LTP and memory are maintained without PKMζ in PKMζ-null mice. Two hypotheses can account for these findings. First, PKMζ is unimportant for LTP or memory. Second, PKMζ is essential for late-LTP and long-term memory in wild-type mice, and PKMζ-null mice recruit compensatory mechanisms. We find that whereas PKMζ persistently increases in LTP maintenance in wild-type mice, PKCι/λ, a gene-product closely related to PKMζ, persistently increases in LTP maintenance in PKMζ-null mice. Using a pharmacogenetic approach, we find PKMζ-antisense in hippocampus blocks late-LTP and spatial long-term memory in wild-type mice, but not in PKMζ-null mice without the target mRNA. Conversely, a PKCι/λ-antagonist disrupts late-LTP and spatial memory in PKMζ-null mice but not in wild-type mice. Thus, whereas PKMζ is essential for wild-type LTP and long-term memory, persistent PKCι/λ activation compensates for PKMζ loss in PKMζ-null mice.

DOI:http://dx.doi.org/10.7554/eLife.14846.001

How are long-term memories stored in the brain? The formation of memories is believed to depend on the strengthening of connections between neurons. During learning, neurons produce an enzyme called PKMzeta (or PKMζ), which is thought to be responsible for maintaining the newly strengthened connections. Inhibitors of PKMzeta, such as a drug called ZIP, disrupt long-term memories. This suggests that the brain may be like a computer hard disc in that its stored information — its memories — could be erased.

However, recent experiments on genetically engineered mice have thrown the role of PKMzeta into question. Knockout mice that lack the gene for PKMzeta can still strengthen connections between neurons and can still learn and remember. Moreover, ZIP still works to reverse the strengthening and to erase long-term memories. This indicates that ZIP can act on something other than the PKMzeta enzyme. These results have led many neuroscientists to doubt that PKMzeta has anything to do with memory.

Yet there are two possible explanations for the normal memory in PKMzeta knockout mice. First, PKMzeta is not required for memory, so getting rid of it has no effect. Second, PKMzeta is essential for long-term memory in normal mice. However, knockout mice recruit a back-up mechanism for long-term memory storage, which is also sensitive to the effects of ZIP.

To test these possibilities, Tsokas et al. used a modified piece of DNA that prevents neurons with the gene for PKMzeta from producing the enzyme. The DNA blocked memory formation in normal mice, consistent with a role for PKMzeta in memory. However, it had no effect in knockout mice — the DNA had nothing to work on. This suggests that another molecule does indeed act as a back-up for PKMzeta in these animals. Further experiments revealed that an enzyme closely related to PKMzeta, called PKCiota/lambda (PKCι/λ), substitutes for PKMzeta during memory storage in the knockout mice.

These findings restore PKMzeta to its early promise. They show that PKMzeta is crucial for long-term memory in normal mice, but that something as important as memory storage has a back-up mechanism should PKMzeta fail. Future work may reveal when and how this back-up becomes engaged.

DOI:http://dx.doi.org/10.7554/eLife.14846.002

• LTP
• PKCiota/lambda
• PKM-zeta
• PKMzeta
• atypical PKC
• memory
• mouse
• neuroscience

• ACC
• ACC = anterior cingulate cortex
• DBS = deep brain stimulation
• DTI = diffusion tensor imaging
• IASP = International Association for the Study of Pain
• IC = internal capsule
• LTP = long-term potentiation
• MRS = MR spectroscopy
• PAG = periaqueductal gray
• PVG = periventricular gray
• VAS = visual analog scale
• VPLA/PM = ventral posterior lateral and medial thalamic nuclei
• anterior cingulate cortex
• chronic pain
• dACC
• dACC = dorsal ACC
• deep brain stimulation
• fMRI = functional MRI
• neuropathic pain

• brain-gut interaction
• fMRI
• irritable bowel syndrome
• visceral sensitivity

Diabetic neuropathy is a common complication of both type 1 and type 2 diabetes, which affects over 90% of the diabetic patients. Although pain is one of the main symptoms of diabetic neuropathy, its pathophysiological mechanisms are not yet fully known. It is widely accepted that the toxic effects of hyperglycemia play an important role in the development of this complication, but several other hypotheses have been postulated. The management of diabetic neuropathic pain consists basically in excluding other causes of painful peripheral neuropathy, improving glycemic control as a prophylactic therapy and using medications to alleviate pain. First line drugs for pain relief include anticonvulsants, such as pregabalin and gabapentin and antidepressants, especially those that act to inhibit the reuptake of serotonin and noradrenaline. In addition, there is experimental and clinical evidence that opioids can be helpful in pain control, mainly if associated with first line drugs. Other agents, including for topical application, such as capsaicin cream and lidocaine patches, have also been proposed to be useful as adjuvants in the control of diabetic neuropathic pain, but the clinical evidence is insufficient to support their use. In conclusion, a better understanding of the mechanisms underlying diabetic neuropathic pain will contribute to the search of new therapies, but also to the improvement of the guidelines to optimize pain control with the drugs currently available.

• Diabetes
• Neuropathic pain
• Hyperglycemia
• Anticonvulsants
• Antidepressants

• gabapentin
• allodynia
• fdg-pet
• functional connectivity
• neuropathic pain

• Amines/pharmacology
• Amines/therapeutic use
• Animals
• Brain/drug effects
• Brain/metabolism
• Brain/physiopathology
• Cyclohexanecarboxylic Acids/pharmacology
• Cyclohexanecarboxylic Acids/therapeutic use
• Disease Models, Animal
• Fluorodeoxyglucose F18
• Gabapentin
• Glucose/metabolism
• Hyperalgesia/drug therapy
• Hyperalgesia/etiology
• Male
• Neuralgia/drug therapy
• Neuralgia/pathology
• Pain Measurement
• Positron-Emission Tomography
• Prefrontal Cortex/diagnostic imaging
• Prefrontal Cortex/drug effects
• Prefrontal Cortex/metabolism
• Radiography
• Rats
• Rats, Sprague-Dawley
• Tomography Scanners, X-Ray Computed
• gamma-Aminobutyric Acid/pharmacology
• gamma-Aminobutyric Acid/therapeutic use