Journal
JOURNAL OF NEUROSCIENCE
Volume 25, Issue 14, Pages 3551-3559Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4899-04.2005
Keywords
knock-out; opioid; tail-flick; Kir3; pain; nociception
Categories
Funding
- NIDA NIH HHS [DA00564, R01 DA000564, T32 DA007234, R56 DA000564, DA01583, R01 DA001583, T32 DA07234, P50 DA011806] Funding Source: Medline
- NIMH NIH HHS [MH61933, R01 MH061933] Funding Source: Medline
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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 mu-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 kappa 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 delta-selective opioid agonists evoke analgesia.
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