Interaction with Vesicle Luminal Protachykinin Regulates Surface Expression of [delta]-Opioid Receptors and Opioid Analgesia

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2005.06.010 Byline: Ji-Song Guan (1)(3), Zhen-Zhong Xu (1)(3), Hua Gao (2), Shao-Qiu He (1), Guo-Qiang Ma (2), Tao Sun (1), Li-Hua Wang (1), Zhen-Ning Zhang (2), Isabelle Lena (6), Ian Kitchen (6), Robert Elde (5), Andreas Zimmer (4), Cheng He (1), Gang Pei (2), Lan Bao (2), Xu Zhang (1) Abstract: Opioid 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. Author Affiliation: (1) Institute of Neuroscience, Key Laboratory of Neurobiology, Chinese Academy of Sciences, Shanghai 200031, China (2) Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, SIBS, Chinese Academy of Sciences, Shanghai 200031, China (3) Graduate School of CAS, Chinese Academy of Sciences, Shanghai 200031, China (4) Department of Psychiatry, University of Bonn, Bonn 53105, Germany (5) Department of Cell Biology and Neuroanatomy, University of Minnesota, Minneapolis, Minnesota 55108 (6) Pharmacology Group, School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey GU2 7XH, United Kingdom Article History: Received 17 December 2004; Revised 11 April 2005; Accepted 7 June 2005 Article Note: (miscellaneous) Published: August 25, 2005