GIRK channels were first implicated in pain perception when opioid analgesia was tested in weaver mice that carry a spontaneous mutation in the pore region of GIRK2132 leading to a loss of K+ selectivity and G-protein insensitivity (GIRK2wv)22,133,134. Upon receptor activation GIRK2wv depolarizes rather than hyperpolarizes neurons. Morphine and a selective κ opioid agonist (U-50488) that are known to activate GIRK2-containing channels through opioid receptors reduce pain perception in wild-type mice, but not in the weaver mice135. The interpretation of the opioid-dependent behaviors, however, is confounded by the loss of neurons in the substantia nigra and cerebellum136.
