Role of opioid receptor heterodimerization in pain modulation and tolerance development

Table 1 Alteration of receptor properties by heteromerization over the years

Year of study	Receptors involved	Mode of study	Possible mechanismfor interaction	Changes inbinding properties	Heteromerspecific ligands	Changes in G-proteinactivation and coupling	Possible therapeutic implications	Ref.
2000	MOR/DOR	In vivo	Direct interaction (heterodimers are preferred)	Decrease in affinity for selective agonists			Pain relief	George et al[9]
2000	MOR/DOR	In vivo	Direct interaction (heterodimers are preferred)	Allosteric effect of DOR ligands on MOR binding			Pain relief	Gomes et al[10]
2004	MOR/DOR	In vivo	Direct interaction (heterodimers are preferred)			Decrease in G protein coupling	Pain relief	Gomes et al[19]
2000	MOR/DOR	In vivo	Direct interaction (heterodimers are preferred)			Allosteric effect of DOR ligands on MOR coupling; signaling through a β-arrestin2-mediated pathway	Pain relief	Rozenfeld et al[6]
2007	MOR/DOR					Shift in coupling from Gαi to Gαz	Pain relief	Hasbi et al[84]
2005	MOR/DOR	COS-7 and CHO-K1 cells	Direct interaction (heterodimers are preferred)				Pain relief, tolerance development	Fan et al[46]
2003	KOR/DOR	Mouse spinal cord	Direct interaction (heterodimers are preferred)				Pain relief	Portoghese et al[45]
2001	KOR/DOR	Porcine ileum	Direct interaction (heterodimers are preferred)				Pain relief	Poonyachoti et al[44]
2010	MOR/DOR	HEK-293 cells	Direct interaction (heterodimers are preferred)				Pain relief	Yekkirala et al[57]
2005	MOR/DOR	In vivo	Direct interaction (heterodimers are preferred)		Specific heteromer activation by the agonist 6-GNTI		Pain relief	Waldhoer et al[43]
2014	DOR/KOR	In vivo (rat trigeminal ganglia)	Allosteric interactions				Thermal allodynia	Erbs et al[11]

MOR: Mu homologous opioid G-protein coupled receptors; DOR: Delta homologous opioid G-protein coupled receptors; KOR: Kappa homologous opioid G-protein coupled receptors.