Cell-autonomous regulation of mu-opioid receptor recycling by substance P

Shanna L. Bowman, Amanda L. Soohoo, Daniel J. Shiwarski, Stefan Schulz, Amynah A. Pradhan, Manojkumar A. Puthenveedu

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


How neurons coordinate and reprogram multiple neurotransmitter signals is an area of broad interest. Here, we show that substance P (SP), a neuropeptideassociated 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 inrecycling and resensitization. Furthermore, SP enhances the resensitization of fentanyl-induced, but not morphine-induced, antinociception in mice. Ourresults 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.

Original languageEnglish
Pages (from-to)1925-1936
Number of pages12
JournalCell Reports
Issue number11
StatePublished - Mar 24 2015


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