Cell-Autonomous Regulation of Mu-Opioid Receptor Recycling by Substance P

• Main Authors: Shanna L. Bowman, Amanda L. Soohoo, Daniel J. Shiwarski, Stefan Schulz, Amynah A. Pradhan, Manojkumar A. Puthenveedu
• Format: Article
• Language: English
• Published: Elsevier 2015-03-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S221112471500203X

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.