Knockout studies also suggest that GIRK channels may account for gender difference in nociception. The higher pain threshold in males, measured as a longer latency for tail withdrawal to radiant heat, is abolished in GIRK2−/− mice137, indicating that GIRK channel activation may account for some of the gender differences in normal pain perception. Further evidence for this notion came from a study that showed the analgesic effects of ethanol, oxotremorine (muscarinic receptor agonist), baclofen (GABAB receptor agonist), clonidine (α2 receptor agonist) and WIN 55,212-2 (cannabinoid receptor agonist) reduced or eliminated in male but not female GIRK2−/− mice138. Studies using mice lacking GIRK1 or GIRK2 channels show a blunted response to μ- ([D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin, DAMGO) and ∂-(Tyr-D-Ala-Phe-Glu-Val-Val-Gly amide) but not κ-opioid receptor ((trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methanesulfonate hydrate) agonists when applied intrathecally139. Similarly, intrathecal tertiapin, a selective GIRK channel inhibitor123, reduced the efficiency of DAMGO to increase the latency for withdrawal in the immersion tail-flick test. Therefore, while further studies are needed to clarify the role of GIRK channels in opioid-induced analgesia, there is general agreement that GIRK channels modulate systemic opioid (or Gio)-mediated analgesia through postsynaptic inhibition.
