Bowman Shanna L, Soohoo Amanda L, Shiwarski Daniel J, Schulz Stefan, Pradhan Amynah A, Puthenveedu Manojkumar A
Cell Rep. 2015 Mar 24;10(11):1925-36. doi: 10.1016/j.celrep.2015.02.045.
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.
神经元如何协调和重新编程多种神经递质信号是一个备受广泛关注的领域。在此，我们表明，与炎性疼痛相关的神经肽P物质（SP）可重新编程阿片受体的循环利用和信号传导。SP通过激活神经激肽1（NK1R）受体，以激动剂选择性方式增加三叉神经节（TG）神经元中μ-阿片受体（MOR）的内吞后循环。SP介导的蛋白激酶C（PKC）激活对于增加TG神经元中外源性和内源性MOR的循环是必需且充分的。鉴于MOR上两个PKC磷酸化位点中的任何一个发生突变都会消除SP诱导的循环增加和再敏化，这种交叉调节的靶点是MOR本身。此外，SP增强了小鼠中芬太尼诱导的而非吗啡诱导的镇痛再敏化。我们的结果定义了一条通过直接修饰MOR来交叉调节阿片受体循环的生理途径，并提示了疼痛和镇痛系统之间的稳态相互作用模式。
