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

While opioids produce both analgesia and side effects by action at mu-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 beta-arrestin versus G-protein alpha-subunits (G alpha), recent studies suggest that G-protein-biased MOR agonists still produce clinically important side effects. Since bias also exists in the role of G alpha subunits, we evaluated the role of G alpha(i/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 G alpha(i)2, G alpha(i)3, and G alpha(o) markedly attenuated hyperalgesia induced by subanalgesic dose (sub-AD) fentanyl, while AS-ODN for G alpha(i)1, as well as G alpha(i)2 and G alpha(i)3, but not G alpha(o), prevented hyperalgesia induced by sub-AD morphine. AS-ODN for G alpha(i)1 and G alpha(i)2 unexpectedly enhanced analgesia induced by analgesic dose (AD) fentanyl, while G alpha(i)1 AS-ODN markedly reduced AD morphine analgesia. Hyperalgesic priming, assessed by prolongation of prostaglandin E-2-induced hyperalgesia, was not produced by systemic sub-AD and AD fentanyl in G alpha(i)3 and G alpha(o) AS-ODN-treated rats, respectively. In contrast, none of the G alpha(i/o) AS-ODNs tested affected priming induced by systemic sub-AD and AD morphine. We conclude that signaling by different G alpha(i/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 G alpha(i/o) may produce a more limited range of side effects and enhanced analgesia.