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: Michelle R Hoot, Elizabeth I Sypek, Kate J Reilley, Amanda N Carey, Jean M Bidlack, Jay P McLaughlin
• Journal: Behavioural pharmacology (Behav Pharmacol) Vol. 24 Issue 2 Pg. 144-52 (Apr 2013) ISSN: 1473-5849 [Electronic] England
• PMID: 23412114 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Analgesics, Opioid
• G-protein Beta gamma
• GTP-Binding Protein beta Subunits
• GTP-Binding Protein gamma Subunits
• Receptors, Opioid, mu
• Xanthenes
• Morphine
• gallein

Topics

• Analgesics, Opioid (administration & dosage, adverse effects, agonists, therapeutic use)
• Animals
• Behavior, Animal (drug effects)
• Constipation (chemically induced, prevention & control)
• Dose-Response Relationship, Drug
• Drug Therapy, Combination
• Drug Tolerance
• GTP-Binding Protein beta Subunits (antagonists & inhibitors)
• GTP-Binding Protein gamma Subunits (antagonists & inhibitors)
• Hyperkinesis (chemically induced, prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Morphine (administration & dosage, adverse effects, agonists, therapeutic use)
• Motor Activity (drug effects)
• Pain Measurement
• Receptors, Opioid, mu (agonists)
• Respiratory Insufficiency (chemically induced, prevention & control)
• Reward
• Second Messenger Systems (drug effects)
• Xanthenes (therapeutic use)