title: Inhibition of Gβγ-subunit signaling potentiates morphine-induced antinociception but not respiratory depression, constipation, locomotion, and reward.
abstract: Inhibition of Gβγ-subunit signaling to phospholipase C β3 has been shown to potentiate morphine-mediated antinociception while attenuating the development of tolerance and dependence in mice. The objective of this study was to determine the effect of Gβγ-subunit inhibition on antinociception and other pharmacological effects, such as respiratory depression, constipation, and hyperlocomotion, mediated by the μ-opioid receptor. The Gβγ-subunit inhibitor, gallein, was administered to C57BL/6J mice by intraperitoneal injection before morphine, and data were compared with mice treated with vehicle, morphine, or gallein alone. Morphine-induced antinociception was measured using the 55°C warm-water tail-withdrawal test. Pretreatment with gallein produced a dose-dependent potentiation of morphine-mediated antinociception, producing up to a 10-fold leftward shift in the morphine dose-response curve and extending the duration of antinociception induced by a single dose of morphine. Gallein pretreatment also prevented acute antinociceptive tolerance induced by morphine. In contrast, the dose-dependent respiratory depression and hyperlocomotion induced by morphine were not potentiated by gallein pretreatment. Similarly, gallein pretreatment did not potentiate morphine-conditioned place preference responses or morphine-induced constipation, as measured as a reduction in excreta. These results suggest that selectively inhibiting Gβγ-mediated signaling may selectively increase μ-opioid receptor-mediated antinociception without matching increases in adverse physiological effects.
authors: Torrey Pines Institute of Molecular Studies, Port St Lucie, Florida 34987, USA.
authors: Michelle R
authors: MR
authors: Hoot
authors: Elizabeth I
authors: EI
authors: Sypek
authors: Kate J
authors: KJ
authors: Reilley
authors: Amanda N
authors: AN
authors: Carey
authors: Jean M
authors: JM
authors: Bidlack
authors: Jay P
authors: JP
authors: McLaughlin
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000819:agonists* / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003248:Constipation / Q000139:chemically induced / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004361:Drug Tolerance; D044387:GTP-Binding Protein beta Subunits / Q000037:antagonists & inhibitors*; D044388:GTP-Binding Protein gamma Subunits / Q000037:antagonists & inhibitors*; D006948:Hyperkinesis / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects / Q000819:agonists* / Q000627:therapeutic use; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement; D017450:Receptors, Opioid, mu / Q000819:agonists; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000517:prevention & control*; D012201:Reward; D015290:Second Messenger Systems / Q000187:drug effects; D014966:Xanthenes / Q000627:therapeutic use*
chemical_list: D000701:Analgesics, Opioid; C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D017450:Receptors, Opioid, mu; D014966:Xanthenes; D009020:Morphine; C007820:gallein