PMID- 34965973 OWN - NLM STAT- MEDLINE DCOM- 20220225 LR - 20220817 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 42 IP - 7 DP - 2022 Feb 16 TI - Contribution of G-Protein alpha-Subunits to Analgesia, Hyperalgesia, and Hyperalgesic Priming Induced by Subanalgesic and Analgesic Doses of Fentanyl and Morphine. PG - 1196-1210 LID - 10.1523/JNEUROSCI.1982-21.2021 [doi] AB - 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 (Galpha), recent studies suggest that G-protein-biased MOR agonists still produce clinically important side effects. Since bias also exists in the role of Galpha subunits, we evaluated the role of Galpha(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 Galpha(i)2, Galpha(i)3, and Galpha(o) markedly attenuated hyperalgesia induced by subanalgesic dose (sub-AD) fentanyl, while AS-ODN for Galpha(i)1, as well as Galpha(i)2 and Galpha(i)3, but not Galpha(o), prevented hyperalgesia induced by sub-AD morphine. AS-ODN for Galpha(i)1 and Galpha(i)2 unexpectedly enhanced analgesia induced by analgesic dose (AD) fentanyl, while Galpha(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 Galpha(i)3 and Galpha(o) AS-ODN-treated rats, respectively. In contrast, none of the Galpha(i/o) AS-ODNs tested affected priming induced by systemic sub-AD and AD morphine. We conclude that signaling by different Galpha(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 Galpha(i/o) may produce a more limited range of side effects and enhanced analgesia.SIGNIFICANCE STATEMENT Biased mu-opioid receptor (MOR) agonists that preferentially signal through G-protein alpha-subunits over beta-arrestins have been developed as an approach to mitigate opioid side effects. However, we recently demonstrated that biased MOR agonists also produce hyperalgesia and priming. We show that oligodeoxynucleotide antisense to different Galpha(i/o) subunits play a role in hyperalgesia and analgesia induced by subanalgesic and analgesic dose (respectively), of fentanyl and morphine, as well as in priming. Our findings have the potential to advance our understanding of the mechanisms involved in adverse effects of opioid analgesics that could assist in the development of novel analgesics, preferentially targeting specific G-protein alpha-subunits. CI - Copyright (c) 2022 the authors. FAU - Araldi, Dioneia AU - Araldi D AUID- ORCID: 0000-0001-8379-2901 AD - Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, California 94143 Dioneia.Araldi@ucsf.edu Jon.Levine@ucsf.edu. FAU - Bonet, Ivan J M AU - Bonet IJM AD - Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, California 94143. FAU - Green, Paul G AU - Green PG AD - Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, California 94143. AD - Department of Preventative and Restorative Dental Sciences, Division of Neuroscience, University of California at San Francisco, San Francisco, California 94143. FAU - Levine, Jon D AU - Levine JD AUID- ORCID: 0000-0003-0681-5545 AD - Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, California 94143 Dioneia.Araldi@ucsf.edu Jon.Levine@ucsf.edu. AD - Department of Medicine, Division of Neuroscience, University of California at San Francisco, San Francisco, California 94143. LA - eng GR - R01 NS084545/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20211229 PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Analgesics, Opioid) RN - 0 (GTP-Binding Protein alpha Subunits) RN - 76I7G6D29C (Morphine) RN - UF599785JZ (Fentanyl) SB - IM MH - *Analgesia MH - Analgesics, Opioid/*pharmacology MH - Animals MH - Fentanyl/*pharmacology MH - GTP-Binding Protein alpha Subunits/*metabolism MH - Hyperalgesia/*chemically induced MH - Male MH - Morphine/*pharmacology MH - Rats MH - Rats, Sprague-Dawley PMC - PMC8883871 OTO - NOTNLM OT - G-protein OT - analgesia OT - fentanyl OT - hyperalgesic priming OT - morphine OT - opioid-induced hyperalgesia EDAT- 2021/12/31 06:00 MHDA- 2022/02/26 06:00 PMCR- 2022/08/16 CRDT- 2021/12/30 05:27 PHST- 2021/10/01 00:00 [received] PHST- 2021/12/09 00:00 [revised] PHST- 2021/12/15 00:00 [accepted] PHST- 2021/12/31 06:00 [pubmed] PHST- 2022/02/26 06:00 [medline] PHST- 2021/12/30 05:27 [entrez] PHST- 2022/08/16 00:00 [pmc-release] AID - JNEUROSCI.1982-21.2021 [pii] AID - JN-RM-1982-21 [pii] AID - 10.1523/JNEUROSCI.1982-21.2021 [doi] PST - ppublish SO - J Neurosci. 2022 Feb 16;42(7):1196-1210. doi: 10.1523/JNEUROSCI.1982-21.2021. Epub 2021 Dec 29.