Mu-opioid receptor coupling to gα o plays an important role in opioid antinociception

Abstract

Opioid analgesics elicit their effects via activation of the mu-opioid receptor (MOR), a G protein-coupled receptor known to interact with Gα i/o-type G proteins. Work in vitro has suggested that MOR couples preferentially to the abundant brain Gα i/o isoform, Gα o. However, studies in vivo evaluating morphine-mediated antinociception have not supported these findings. The aim of the present work was to evaluate the contribution of Gα o to MOR-dependent signaling by measuring both antinociceptive and biochemical endpoints in a Gα o null transgenic mouse strain. Male wild-type and Gα o heterozygous null (Gα o/) mice were tested for opioid antinociception in the hot plate test or the warm-water tail withdrawal test as measures of supraspinal or spinal antinociception, respectively. Reduction in Gα o levels attenuated the supraspinal antinociception produced by morphine, methadone, and nalbuphine, with the magnitude of suppression dependent on agonist efficacy. This was explained by a reduction in both high-affinity MOR expression and MOR agonist-stimulated G protein activation in whole brain homogenates from Gα o/and Gα o homozygous null (Gα o/) mice, compared with wild-type littermates. On the other hand, morphine spinal antinociception was not different between Gα o/and wild-type mice and high-affinity MOR expression was unchanged in spinal cord tissue. However, the action of the partial agonist nalbuphine was compromised, showing that reduction in Gα o protein does decrease spinal antinociception, but suggesting a higher Gα o protein reserve. These results provide the first in vivo evidence that Gα o contributes to maximally efficient MOR signaling and antinociception. © 2011 American College of Neuropsychopharmacology. All rights reserved.