Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS

Significance Many classes of G protein-coupled receptors (GPCRs) produce truncated variants. Truncated forms of the mu opioid receptor gene Oprm1 containing only six transmembrane domains (6TM) can mediate a potent analgesia without producing many classical opioid side effects. We now show that 6TM Oprm1 splice variants are essential in the analgesic actions of delta and kappa opioids as well as α2 adrenergic drugs, but not neurotensin, cannabinoids, or muscarinic drugs. The role of the 6TM variants seems limited to analgesia because they are not involved with kappa aversion, delta-induced seizure activity, or α2 adrenergic hypolocomotion. These findings emphasize the importance of 6TM Oprm1 variants in opioid and nonopioid sensory processing and illustrate the potential importance of the vast array of other classes of truncated GPCR variants. The clinical management of severe pain depends heavily on opioids acting through mu opioid receptors encoded by the Oprm1 gene, which undergoes extensive alternative splicing. In addition to generating a series of prototypic seven transmembrane domain (7TM) G protein-coupled receptors (GPCRs), Oprm1 also produces a set of truncated splice variants containing only six transmembrane domains (6TM) through which selected opioids such as IBNtxA (3′-iodobenzoyl-6β-naltrexamide) mediate a potent analgesia without many undesirable effects. Although morphine analgesia is independent of these 6TM mu receptor isoforms, we now show that the selective loss of the 6TM variants in a knockout model eliminates the analgesic actions of delta and kappa opioids and of α2-adrenergic compounds, but not cannabinoid, neurotensin, or muscarinic drugs. These observations were confirmed by using antisense paradigms. Despite their role in analgesia, loss of the 6TM variants were not involved with delta opioid-induced seizure activity, aversion to the kappa drug U50,488H, or α2-mediated hypolocomotion. These observations support the existence of parallel opioid and nonopioid pain modulatory systems and highlight the ability to dissociate unwanted delta, kappa1, and α2 actions from analgesia.

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