Contribution of G-Protein a-Subunits to Analgesia, Hyperalgesia, and Hyperalgesic Priming Induced by Subanalgesic and Analgesic Doses of Fentanyl and Morphine

Abstract

While opioids produce both analgesia and side effects by action at l-opioid receptors (MORs), at spinal and supraspinal sites, the potency of different opioids to produce these effects varies. While it has been suggested that these differences might be because of bias for signaling via b-arrestin versus G-protein a-subunits (Ga), recent studies suggest that G-protein-biased MOR agonists still produce clinically important side effects. Since bias also exists in the role of Ga subunits, we evaluated the role of Gai/o subunits in analgesia, hyperalgesia, and hyperalgesic priming produced by fentanyl and morphine, in male rats. We found that intrathecal treatment with oligodeoxynucleotides antisense (AS-ODN) for Gai2, Gai3, and Gao markedly attenuated hyperalgesia induced by subanalgesic dose (sub-AD) fentanyl, while AS-ODN for Gai1, as well as Gai2 and Gai3, but not Gao, prevented hyperalgesia induced by sub-AD morphine. AS-ODN for Gai1 and Gai2 unexpectedly enhanced analgesia induced by analgesic dose (AD) fentanyl, while Gai1 AS-ODN markedly reduced AD morphine analgesia. Hyperalgesic priming, assessed by prolongation of prostaglandin E2-induced hyperalgesia, was not produced by systemic sub-AD and AD fentanyl in Gai3 and Gao AS-ODN-treated rats, respectively. In contrast, none of the Gai/o AS-ODNs tested affected priming induced by systemic sub-AD and AD morphine. We conclude that signaling by different Gai/o subunits is necessary for the analgesia and side effects of two of the most clinically used opioid analgesics. The design of opioid analgesics that demonstrate selectivity for individual Gai/o may produce a more limited range of side effects and enhanced analgesia.