Mu-Opioid Receptor Coupling to Gαo Plays an Important Role in Opioid Antinociception

Opioid analgesics elicit their effects via activation of the mu-opioid receptor (MOR), a G protein-coupled receptor known to interact with G alpha(i/o)-type G proteins. Work in vitro has suggested that MOR couples preferentially to the abundant brain G alpha(i/o) isoform, G alpha(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 G alpha(o) to MOR-dependent signaling by measuring both antinociceptive and biochemical endpoints in a G alpha(o) null transgenic mouse strain. Male wild-type and G alpha(o) heterozygous null (G alpha(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 G alpha(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 G alpha(o) +/- and G alpha(o) homozygous null (G alpha(o) -/-) mice, compared with wild-type littermates. On the other hand, morphine spinal antinociception was not different between G alpha(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 G alpha(o) protein does decrease spinal antinociception, but suggesting a higher G alpha(o) protein reserve. These results provide the first in vivo evidence that G alpha(o) contributes to maximally efficient MOR signaling and antinociception. Neuropsychopharmacology (2011) 36, 2041-2053; doi: 10.1038/npp.2011.91; published online 8 June 2011