Contribution of GIRK2-mediated postsynaptic signaling to opiate and alpha 2-adrenergic analgesia and analgesic sex differences.
The analgesia produced by inhibitory G protein-coupled receptor agonists involves coordinated postsynaptic inhibition via G protein-coupled inwardly rectifying potassium channels (GIRKs) and presynaptic inhibition of neurotransmitter release through regulation of voltage-gated Ca(2+) channels. Here, we used mice lacking the GIRK2 channel subunit to assess the relative contribution of these two effector systems to nociceptive processing in male and female mice. Compared with female WT mice, male WT mice exhibited higher pain thresholds and enhanced opioid (morphine) and alpha(2)-adrenergic (clonidine) receptor-induced antinociception in a spinal reflex test. The GIRK2-null mutation reduced the "pain" threshold in male but not in female mice, effectively eliminating the sex differences in pain threshold. In addition, deletion of GIRK2 channels in mutant mice largely eliminated clonidine antinociception and significantly decreased morphine antinociception. Furthermore, the more pronounced morphine and clonidine-induced antinociception in male mice disappeared in the GIRK2 mutants. Based on the almost complete loss of clonidine-induced antinociception in the mutant mice, we conclude that it is primarily mediated by postsynaptic alpha(2)-adrenergic receptors. In contrast, the significant residual morphine effect in the mutant mice points to the presynaptic mu opioid receptor as a major contributor to its analgesic action. Finally, our results suggest that the reduced pain responsiveness of male compared with female mice results in part from GIRK2-coupled postsynaptic receptors that are activated by endogenous antinociceptive systems.
Mitrovic
Igor
I
Department of Physiology, University of California, San Francisco, 94143, USA.
Margeta-Mitrovic
Marta
M
Bader
Semon
S
Stoffel
Markus
M
Jan
Lily Y
LY
Basbaum
Allan I
AI
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000698:Analgesia; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D003000:Clonidine / Q000494:pharmacology*; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D005727:Ganglia, Spinal / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D010146:Pain / Q000235:genetics / Q000503:physiopathology*; D017288:Pain Threshold; D015221:Potassium Channels / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D021122:Protein Subunits; D012727:Sex Characteristics; D015398:Signal Transduction; D013116:Spinal Cord / Q000502:physiology; D013569:Synapses / Q000502:physiology*
D000316:Adrenergic alpha-Agonists; D000700:Analgesics; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D021122:Protein Subunits; D009020:Morphine; D003000:Clonidine