title: μ-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.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Jennifer T
authors.initials: JT
authors.lastname: Lamberts
authors.forename: Emily M
authors.initials: EM
authors.lastname: Jutkiewicz
authors.forename: Richard M
authors.initials: RM
authors.lastname: Mortensen
authors.forename: John R
authors.initials: JR
authors.lastname: Traynor
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism*; D000818:Animals; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D011485:Protein Binding / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D019206:GTP-Binding Protein alpha Subunits, Gi-Go