• Ji-Song Guan, Zhen-Zhong Xu, Hua Gao, Shao-Qiu He, Guo-Qiang Ma, Tao Sun, Li-Hua Wang, Zhen-Ning Zhang, Isabelle Lena, Ian Kitchen, Robert Elde, Andreas Zimmer, Cheng He, Gang Pei, Lan Bao, and Xu Zhang.
• Institute of Neuroscience, Key Laboratory of Neurobiology, Chinese Academy of Sciences, Shanghai 200031, China.
• Cell. 2005 Aug 26;122(4):619-31.

AbstractOpioid and tachykinin systems are involved in modulation of pain transmission in the spinal cord. Regulation of surface opioid receptors on nociceptive afferents is critical for opioid analgesia. Plasma-membrane insertion of delta-opioid receptors (DORs) is induced by stimulus-triggered exocytosis of DOR-containing large dense-core vesicles (LDCVs), but how DORs become sorted into the regulated secretory pathway is unknown. Here we report that direct interaction between protachykinin and DOR is responsible for sorting of DORs into LDCVs, allowing stimulus-induced surface insertion of DORs and DOR-mediated spinal analgesia. This interaction is mediated by the substance P domain of protachykinin and the third luminal domain of DOR. Furthermore, deletion of the preprotachykinin A gene reduced stimulus-induced surface insertion of DORs and abolished DOR-mediated spinal analgesia and morphine tolerance. Thus, protachykinin is essential for modulation of the sensitivity of nociceptive afferents to opioids, and the opioid and tachykinin systems are directly linked by protachykinin/DOR interaction.

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