Abstract
Opioid analgesics elicit their effects via activation of the mu-opioid receptor (MOR), a G protein-coupled receptor known to interact with Gαi/o-type G proteins. Work in vitro has suggested that MOR couples preferentially to the abundant brain Gαi/o isoform, Gαo. 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 Gαo to MOR-dependent signaling by measuring both antinociceptive and biochemical endpoints in a Gαo null transgenic mouse strain. Male wild-type and Gαo heterozygous null (Gαo +/−) 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 Gαo 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 Gαo +/− and Gαo homozygous null (Gαo −/−) mice, compared with wild-type littermates. On the other hand, morphine spinal antinociception was not different between Gαo +/− 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 Gαo protein does decrease spinal antinociception, but suggesting a higher Gαo protein reserve. These results provide the first in vivo evidence that Gαo contributes to maximally efficient MOR signaling and antinociception.
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Acknowledgements
We acknowledge Jasmine Schimmel, Chelsea Smith, and Alexander Delgado for excellent technical assistance and/or animal husbandry. This work was supported by NIDA grant DA04087 (to JRT); JTL was supported by training grants DA007267 and GM007767.
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Lamberts, J., Jutkiewicz, E., Mortensen, R. et al. Mu-Opioid Receptor Coupling to Gαo Plays an Important Role in Opioid Antinociception. Neuropsychopharmacol 36, 2041–2053 (2011). https://doi.org/10.1038/npp.2011.91
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DOI: https://doi.org/10.1038/npp.2011.91
