科研之友
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摘要
The generation of potent opioid analgesics that lack the side effects of traditional opioids may be possible by targeting truncated splice variants of the mu-opioid receptor. mu-Opioids act through GPCRs that are generated from the Oprm1 gene, which undergoes extensive alternative splicing. The most abundant set of Oprm1 variants encode classical full-length 7 transmembrane domain (7TM) g-opioid receptors that mediate the actions of the traditional g-opioid drugs morphine and methadone. In contrast, 3-iodobenzoyl-6 beta-naltrexamide (IBNtxA) is a potent analgesic against thermal, inflammatory, and neuropathic pain that acts independently of 7TM mu-opioid receptors but has no activity in mice lacking a set of 6TM truncated p-opioid receptor splice variants. Unlike traditional opioids, IBNtxA does not depress respiration or result in physical dependence or reward behavior, suggesting it acts through an alternative mu-opioid receptor target. Here we demonstrated that a truncated 6TM splice variant, mMOR-1G, can rescue IBNtxA analgesia in a mu-opioid receptor-deficient mouse that lacks all Oprm1 splice variants, ablating mu-opioid activity in these animals. Intrathecal administration of lentivirus containing the 6TM variant mMOR-1G restored IBNtxA, but not morphine, analgesia in Oprm1-deficient animals. Together, these results confirm that a truncated 6TM GPCR is both necessary and sufficient for IBNtxA analgesia.
- 出版日期2015-7
