Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ethanol affects many functions of the brain and peripheral organs. Here we show that ethanol opens G-protein-activated, inwardly rectifying K + (GIRK) channels, which has important implications for inhibitory regulation of neuronal excitability and heart rate. At pharmacologically relevant concentrations, ethanol activated both brain-type GIRK1/2 and cardiac-type GIRK1/4 channels without interaction with G proteins or second messengers. Moreover, weaver mutant mice, which have a missense mutation in the GIRK2 channel, showed a loss of ethanol-induced analgesia. These results suggest that the GIRK channels in the brain and heart are important target sites for ethanol.
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PMID:Ethanol opens G-protein-activated inwardly rectifying K+ channels. 1057 Apr 86

Opioids and ethanol have been used since ancient times for pain relief. Opioid signaling is mediated by various effectors, including G protein-activated inwardly rectifying potassium (GIRK) channels, adenylyl cyclases, voltage-dependent calcium channels, phospholipase Cbeta(PLCbeta), and mitogen-activated protein kinases, although it has been unclear which effector mediates the analgesic effects of opioids. Ethanol induces a variety of physiological phenomena via various proteins, including GIRK channels rather than via membrane lipids. GIRK channel activation by either G proteins or ethanol is impaired in weaver mutant mice. The mutant mice may therefore serve as a useful animal model for studying the role of GIRK channels in vivo. Reduced analgesia by using either opioids or ethanol in weaver mutant mice suggests that GIRK channels are important effectors in both opioid- and ethanol-induced analgesia. This hypothesis is supported by similar findings in GIRK2 knockout mice. Among the various effectors coupled with opioid receptors and various targets of ethanol, GIRK channels are the only molecules whose involvement in opioid- and ethanol-induced analgesia has been demonstrated in vivo. The GIRK channel is potentially one of the key molecules in furthering the understanding of the pain control system and in developing advanced analgesics with fewer adverse effects.
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PMID:Molecular mechanisms of analgesia induced by opioids and ethanol: is the GIRK channel one of the keys? 1235 27

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, alpha adrenergic, muscarinic cholinergic, gamma-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.
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PMID:A pervasive mechanism for analgesia: activation of GIRK2 channels. 1249 43

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.
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PMID:Contribution of GIRK2-mediated postsynaptic signaling to opiate and alpha 2-adrenergic analgesia and analgesic sex differences. 1249 46

G-protein-gated potassium (K+) channels are found throughout the CNS in which they contribute to the inhibitory effects of neurotransmitters and drugs of abuse. Recent studies have implicated G-protein-gated K+ channels in thermal nociception and the analgesic action of morphine and other agents. Because nociception is subject to complex spinal and supraspinal modulation, however, the relevant locations of G-protein-gated K+ channels are unknown. In this study, we sought to clarify the expression pattern and subunit composition of G-protein-gated K+ channels in the spinal cord and to assess directly their contribution to thermal nociception and morphine analgesia. We detected GIRK1 (G-protein-gated inwardly rectifying K+ channel subunit 1) and GIRK2 subunits, but not GIRK3, in the superficial layers of the dorsal horn. Lack of either GIRK1 or GIRK2 was correlated with significantly lower expression of the other, suggesting that a functional and physical interaction occurs between these two subunits. Consistent with these findings, GIRK1 knock-out and GIRK2 knock-out mice exhibited hyperalgesia in the tail-flick test of thermal nociception. Furthermore, GIRK1 knock-out and GIRK2 knock-out mice displayed decreased analgesic responses after the spinal administration of higher morphine doses, whereas responses to lower morphine doses were preserved. Qualitatively similar data were obtained with wild-type mice after administration of the G-protein-gated K+ channel blocker tertiapin. We conclude that spinal G-protein-gated K+ channels consisting primarily of GIRK1/GIRK2 complexes modulate thermal nociception and mediate a significant component of the analgesia evoked by intrathecal administration of high morphine doses
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PMID:Spinal G-protein-gated K+ channels formed by GIRK1 and GIRK2 subunits modulate thermal nociception and contribute to morphine analgesia. 1502 74

Opioids can evoke analgesia by inhibiting neuronal targets in either the brain or spinal cord, and multiple presynaptic and postsynaptic inhibitory mechanisms have been implicated. The relative significance of presynaptic and postsynaptic inhibition to opioid analgesia is essentially unknown, as are the identities and relevant locations of effectors mediating opioid actions. Here, we examined the distribution of G-protein-gated potassium (GIRK) channels in the mouse spinal cord and measured their contribution to the analgesia evoked by spinal administration of opioid receptor-selective agonists. We found that the GIRK channel subunits GIRK1 and GIRK2 were concentrated in the outer layer of the substantia gelatinosa of the dorsal horn. GIRK1 and GIRK2 were found almost exclusively in postsynaptic membranes of putative excitatory synapses, and a significant degree of overlap with the mu-opioid receptor was observed. Although most GIRK subunit labeling was perisynaptic or extrasynaptic, GIRK2 was found occasionally within the synaptic specialization. Genetic ablation or pharmacologic inhibition of spinal GIRK channels selectively blunted the analgesic effect of high but not lower doses of the mu-opioid receptor-selective agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin. Dose-dependent contributions of GIRK channels to the analgesic effects of the -opioid receptor-selective agonists Tyr-D-Ala-Phe-Glu-Val-Val-Gly amide and [D-Pen(2,5)]-enkephalin were also observed. In contrast, the analgesic effect of the agonist (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methanesulfonate hydrate was preserved despite the absence of GIRK channels. We conclude that the activation of postsynaptic GIRK1 and/or GIRK2-containing channels in the spinal cord dorsal horn represents a powerful, albeit relatively insensitive, means by which intrathecal mu- and -selective opioid agonists evoke analgesia.
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PMID:Spinal G-protein-gated potassium channels contribute in a dose-dependent manner to the analgesic effect of mu- and delta- but not kappa-opioids. 1581 85

Although morphine induces both analgesia and dependence through mu-opioid receptors (MORs), the respective contributions of the intracellular effectors engaged by MORs remain unknown. To examine the contribution of G-protein-gated inwardly rectifying K(+) (GIRK, Kir3) channels to morphine dependence and analgesia, we quantified naloxone-precipitated withdrawal behavior and morphine analgesia using GIRK knock-out ((-/-)) mice. The morphine withdrawal syndrome was strongly attenuated, whereas morphine analgesia was mostly preserved in mice lacking both GIRK2 and GIRK3 (GIRK2/3(-/-) mice). In acute slices containing the locus ceruleus (LC) from GIRK2/3(-/-) mice, the increase in spontaneous firing typically associated with morphine withdrawal was absent. Moreover, although morphine elicited normal presynaptic inhibition in the LC, postsynaptic GIRK currents were completely abolished in GIRK2/3(-/-) mice. Altogether, these data suggested that morphine-evoked postsynaptic inhibition of the LC was required for the induction of dependence. Consistent with this hypothesis, morphine withdrawal behavior was rescued in GIRK2/3(-/-) mice by ablation of adrenergic fibers using the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine. Our data suggest that inhibition of adrenergic tone is required for the induction of dependence, and that channels containing GIRK2 and GIRK3 serve as an inhibitory gate.
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PMID:Absence and rescue of morphine withdrawal in GIRK/Kir3 knock-out mice. 1840 Sep 6

The use of opioid agonists acting outside the central nervous system (CNS) is a promising therapeutic strategy for pain control that avoids deleterious central side effects such as apnea and addiction. In human clinical trials and rat models of inflammatory pain, peripherally restricted opioids have repeatedly shown powerful analgesic effects; in some mouse models however, their actions remain unclear. Here, we investigated opioid receptor coupling to K(+) channels as a mechanism to explain such discrepancies. We found that GIRK channels, major effectors for opioid signalling in the CNS, are absent from mouse peripheral sensory neurons but present in human and rat. In vivo transgenic expression of GIRK channels in mouse nociceptors established peripheral opioid signalling and local analgesia. We further identified a regulatory element in the rat GIRK2 gene that accounts for differential expression in rodents. Thus, GIRK channels are indispensable for peripheral opioid analgesia, and their absence in mice has profound consequences for GPCR signalling in peripheral sensory neurons.
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PMID:The K(+) channel GIRK2 is both necessary and sufficient for peripheral opioid-mediated analgesia. 2381 82

G-protein coupled inwardly rectifying potassium (GIRK) channels are effectors determining degree of analgesia experienced upon opioid receptor activation by endogenous and exogenous opioids. The impact of GIRK-related genetic variation on human pain responses has received little research attention. We used a tag single nucleotide polymorphism (SNP) approach to comprehensively examine pain-related effects of KCNJ3 (GIRK1) and KCNJ6 (GIRK2) gene variation. Forty-one KCNJ3 and 69 KCNJ6 tag SNPs were selected, capturing the known variability in each gene. The primary sample included 311 white patients undergoing total knee arthroplasty in whom postsurgical oral opioid analgesic medication order data were available. Primary sample findings were then replicated in an independent white sample of 63 healthy pain-free individuals and 75 individuals with chronic low back pain (CLBP) who provided data regarding laboratory acute pain responsiveness (ischemic task) and chronic pain intensity and unpleasantness (CLBP only). Univariate quantitative trait analyses in the primary sample revealed that 8 KCNJ6 SNPs were significantly associated with the medication order phenotype (P < .05); overall effects of the KCNJ6 gene (gene set-based analysis) just failed to reach significance (P = .054). No significant KCNJ3 effects were observed. A continuous GIRK Related Risk Score (GRRS) was derived in the primary sample to summarize each individual's number of KCNJ6 "pain risk" alleles. This GRRS was applied to the replication sample, which revealed significant associations (P < .05) between higher GRRS values and lower acute pain tolerance and higher CLBP intensity and unpleasantness. Results suggest further exploration of the impact of KCNJ6 genetic variation on pain outcomes is warranted.
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PMID:Associations between KCNJ6 (GIRK2) gene polymorphisms and pain-related phenotypes. 2399 50

G-protein-activated inwardly rectifying potassium (GIRK) channels are expressed in many tissues and activated by several Gi/o protein-coupled receptors, such as opioid and dopamine receptors, and thus are known to be involved in the modulation of opioid-induced analgesia, pain, and reward. We focused on a GIRK-channel subunit that plays a pivotal role in the brain, GIRK2, and investigated the contribution of genetic variations of the GIRK2 (KCNJ6) gene to individual differences in the sensitivity to opioid analgesia. In our initial linkage disequilibrium analysis, a total of 27 single-nucleotide polymorphisms (SNPs) were selected within and around the regions of the KCNJ6 gene. Among them, the rs2835859 SNP, for which associations with analgesia and pain have not been previously reported, was selected in the exploratory study as a potent candidate SNP associated with opioid analgesic sensitivity. The results were corroborated in further confirmatory study. Interestingly, this SNP was also found to be associated with sensitivity to both cold and mechanical pain, susceptibility to nicotine dependence, and successful smoking cessation. The results indicate that this SNP could serve as a marker that predicts sensitivity to analgesic and pain and susceptibility to nicotine dependence.
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PMID:Association between KCNJ6 (GIRK2) gene polymorphism rs2835859 and post-operative analgesia, pain sensitivity, and nicotine dependence. 2534 42


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