A pervasive mechanism for analgesia: Activation of GIRK2 channels

Abstract

G protein-coupled inwardly rectifying potassium channels (GIRKs) provide a common link between numerous neurotransmitter receptors and the regulation of synaptic transmission. We asked whether GIRKs specify a single behavioral action that is produced by drugs acting on the diverse receptors coupled with GIRKs. By using GIRK2-null mutant mice, we found marked reduction or complete elimination of the antinociceptive (hot plate test) effects of ethanol, oxotremorine, nicotine, baclofen, clonidine, and the cannabinoid receptor agonist WIN 55,212. However, ketamine analgesia remained intact. For most drugs, there was a sex difference in antinociceptive action, and the impact of deletion of the GIRK2 channel was less in female mice. The deletion of the GIRK2 channel blocks the opioid-dependent component of stress-induced analgesia (SIA), whereas nonopioid SIA was not changed. We propose that opioid, ␣ adrenergic, muscarinic cholinergic, ␥-aminobutyric acid-B, and cannabinoid receptors are coupled with postsynaptic GIRK2 channels in vivo. Furthermore, this pathway accounts for essentially all of the antinociceptive effects in males, although females appear to recruit additional signal transduction mechanisms for some analgesic drugs.C hemically and pharmacologically diverse drugs reduce nociceptive responses in humans and in animal models of acute pain. Many of these drugs act through G protein coupled receptors and affect multiple pre-and postsynaptic signaling pathways (1, 2). A key question is whether there is a single G protein signal transduction pathway that is important for antinociceptive actions of many different drugs. One candidate for such a signaling system is the G protein-coupled inwardly rectifying potassium channel (GIRK). This assumption is based in part on the observation that weaver mutant mice have a mutation in GIRK2 and display reduced analgesia after either morphine or -opioid agonist (Ϫ)-U-50488 or ethanol administration (3, 4). However, the weaver mutant is not ideal for assessing the role of GIRK2 because the mutation alters the ion selectivity of GIRK2 and produces neuronal degeneration rather than a simple loss of GIRK2 function (5). Targeted mutation has produced mice lacking the GIRK2 protein; these mice lack postsynaptic responses to several neurotransmitters known to act through G protein coupled receptors, but retain normal presynaptic actions of these receptors (6-8). These mice are viable and similar to wild-type controls in many behavioral tests (9-11) and provide a unique approach to defining the role of GIRK2 in drug actions.GIRKs are activated by M 2 muscarinic, ␣ 2 adrenergic, D 2 dopaminergic, histamine, 5HT 1A , A 1 adenosine, ␥-aminobutyric acid (GABA)-B, , , and ␦ opioid, and somatostatin receptors (12, 13). Because many of these neurotransmitter systems are implicated in antinociception, we tested pharmacologically diverse analgesics in GIRK2 knockout mice by using the hot plate test. Because of known sex differences in sensitivity to druginduced analgesia (14), we compared...

Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Various Antidepressant Drugs

“…Studies using GIRK2-deficient mice and weaver mutant mice, which have mutant GIRK2 channels insensitive to G proteins and ethanol, have shown that the analgesic effects induced by opioids or ethanol are remarkably reduced in these mice, suggesting that the GIRK channel activation induces analgesia (Kobayashi et al, 1999;Ikeda et al, 2000Ikeda et al, , 2002Blednov et al, 2003;Mitrovic et al, 2003). However, our studies have demonstrated that various tricyclic antidepressants and fluoxetine inhibit GIRK channels.…”

“…Recent studies using GIRK2-deficient mice suggested that GIRK activators may be useful for the treatment of epilepsy and pain (Signorini et al, 1997;Ikeda et al, 2002;Blednov et al, 2003). In addition, since GIRK knockout mice show decreased cocaine self-administration (Morgan et al, 2003), selective GIRK channel inhibitors might be potential agents for the treatment of abusers of cocaine.…”

Molecular mechanism underlying ethanol activation of G-protein–gated inwardly rectifying potassium channels

“…Alcohol modulation of GIRK channels regulates neuronal excitability in the brain's reward circuit (11) and underlies forms of alcohol addiction (6,(8)(9)(10)36). Here, we uncovered previously undescribed principles governing alcohol modulation of GIRK channels.…”

Absence and Rescue of Morphine Withdrawal in GIRK/Kir3 Knock-out Mice

“…Studies involving mice with mutant Girk genes have implicated GIRK channels in nociception and the acute analgesic effect of morphine (Ikeda et al, 2000;Blednov et al, 2003;Mitrovic et al, 2003;Marker et al, 2004Marker et al, , 2006. For example, weaver mice, which harbor a mutation in the Girk2 gene, exhibited blunted responses to systemic morphine analgesia as measured by the hot-plate test (Ikeda et al, 2000).…”