TY - JOUR
T1 - Cell-autonomous regulation of mu-opioid receptor recycling by substance P
AU - Bowman, Shanna L.
AU - Soohoo, Amanda L.
AU - Shiwarski, Daniel J.
AU - Schulz, Stefan
AU - Pradhan, Amynah A.
AU - Puthenveedu, Manojkumar A.
N1 - Funding Information:
We thank Dr. Alison Barth, Joanne Steinmiller, Jen Dry-Henich, Dr. Rebecca Seal, and Adam Goldring for providing help with isolation of TG neurons and for critical comments. We thank Drs. Mark von Zastrow and Rachel Vistein for reagents and technical help. We thank Drs. John T. Williams and Seksiri Arttamangkul for generously providing the Alexa 594-conjugated dermorphin. We thank Drs. Adam Linstedt, Tina Lee, Joann Trejo, Peter Friedman, Guillermo Romero, Jean-Pierre Vilardaga, Alessandro Bisello, and Aylin Hanyaloglu for comments and suggestions. S.L.B. was supported by an NIH T32 grant NS007433, A.A.P. was supported by NIH DA031243, and M.A.P. was supported by NIH DA024698 and DA036086.
Publisher Copyright:
© 2015 The Authors.
PY - 2015/3/24
Y1 - 2015/3/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84925654067&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2015.02.045
DO - 10.1016/j.celrep.2015.02.045
M3 - Article
C2 - 25801029
AN - SCOPUS:84925654067
SN - 2211-1247
VL - 10
SP - 1925
EP - 1936
JO - Cell Reports
JF - Cell Reports
IS - 11
ER -