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The generation of potent opioid analgesics that lack the side effects of traditional opioids may be possible by targeting truncated splice variants of the μ-opioid receptor. μ-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) μ-opioid receptors that mediate the actions of the traditional μ-opioid drugs morphine and methadone. In contrast, 3-iodobenzoyl-6β-naltrexamide (IBNtxA) is a potent analgesic against thermal, inflammatory, and neuropathic pain that acts independently of 7TM μ-opioid receptors but has no activity in mice lacking a set of 6TM truncated μ-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 μ-opioid receptor target. Here we demonstrated that a truncated 6TM splice variant, mMOR-1G, can rescue IBNtxA analgesia in a μ-opioid receptor-deficient mouse that lacks all Oprm1 splice variants, ablating μ-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.
Introduction
Traditional opioids are effective against many types of severe pain, but side effects are problematic and opioid efficacy against neuropathic pain is limited. Using biased agonism to develop drugs lacking side effects is one approach to address these limitations (1, 2). An alternative is to pursue novel targets. Recently, a new class of opioid analgesics was described with an unusual pharmacological profile (3-6). IBNtxA (3-iodobenzoyl-6β-naltrexamide), a member of this group, is a potent analgesic against thermal, inflammatory and neuropathic pain, but does not depress respiration or produce physical dependence and shows no reward behavior.
These drugs, exemplified by IBNtxA (4), act through mechanisms distinct from traditional μ drugs. The single-copy μ-opioid receptor Oprm1 creates an array of splice variants through alternative pre-mRNA splicing with patterns conserved from rodents to humans (refs. 7, 8, and Supplemental Figure 1; supplemental material available online with this article; doi:10.1172/ JCI81070DS1). The major set of variants are full-length 7 transmembrane domain (7TM) variants associated with exon 1. A second set of variants is characterized by the replacement of the 94...