title: Cell-autonomous regulation of Mu-opioid receptor recycling by substance P.
abstract: How neurons coordinate and reprogram multiple neurotransmitter signals is an area of broad interest. Here, we show that substance P (SP), a neuropeptide associated with inflammatory pain, reprograms opioid receptor recycling and signaling. SP, through activation of the neurokinin 1 (NK1R) receptor, increases the post-endocytic recycling of the mu-opioid receptor (MOR) in trigeminal ganglion (TG) neurons in an agonist-selective manner. SP-mediated protein kinase C (PKC) activation is both required and sufficient for increasing recycling of exogenous and endogenous MOR in TG neurons. The target of this cross-regulation is MOR itself, given that mutation of either of two PKC phosphorylation sites on MOR abolishes the SP-induced increase in recycling and resensitization. Furthermore, SP enhances the resensitization of fentanyl-induced, but not morphine-induced, antinociception in mice. Our results define a physiological pathway that cross-regulates opioid receptor recycling via direct modification of MOR and suggest a mode of homeostatic interaction between the pain and analgesic systems.
authors: Shanna L
authors: SL
authors: Bowman
authors: Amanda L
authors: AL
authors: Soohoo
authors: Daniel J
authors: DJ
authors: Shiwarski
authors: Stefan
authors: S
authors: Schulz
authors: Amynah A
authors: AA
authors: Pradhan
authors: Manojkumar A
authors: MA
authors: Puthenveedu
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004705:Endocytosis; D005283:Fentanyl / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D059225:Nociception; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013373:Substance P / Q000494:pharmacology*; D012668:Trigeminal Ganglion / Q000166:cytology
chemical_list: D000701:Analgesics, Opioid; D018040:Receptors, Neurokinin-1; D017450:Receptors, Opioid, mu; D013373:Substance P; D009020:Morphine; D011493:Protein Kinase C; D005283:Fentanyl