G protein‐coupled receptor kinase 2 mediates µ‐opioid receptor desensitization in GABAergic neurons of the nucleus raphe magnus

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Abstract
Nucleus raphe magnus (NRM) sends the projection to spinal dorsal horn and inhibits nociceptive transmission. Analgesic effect produced by µ‐opioid receptor agonists including morphine partially results from activating the NRM‐spinal cord pathway. It is generally believed that µ‐opioid receptor agonists disinhibit spinally projecting neurons of the NRM and produce analgesia by hyperpolarizing GABAergic interneurons. In the present study, whole‐cell patch‐clamp recordings combined with single‐cell RT‐PCR analysis were used to test the hypothesis that DAMGO ([D‐Ala2,N‐methyl‐Phe4,Gly‐ol5]enkephalin), a specific µ‐opioid receptor agonist, selectively hyperpolarizes NRM neurons expressing mRNA of glutamate decarboxylase (GAD67). Homologous desensitization of µ‐opioid receptors in NRM neurons could result in the development of morphine‐induced tolerance. G protein‐coupled receptor kinase (GRK) is believed to mediate µ‐opioid receptor desensitization in vivo. Therefore, we also investigated the involvement of GRK in mediating homologous desensitization of DAMΑΜGO‐induced electrophysiological effects on NRM neurons by using two experimental strategies. First, single‐cell RT‐PCR assay was used to study the expression of GRK2 and GRK3 mRNAs in individual DAMGO‐responsive NRM neurons. Whole‐cell recording was also performed with an internal solution containing the synthetic peptide, which corresponds to Gβγ‐binding domain of GRK and inhibits Gβγ activation of GRK. Our results suggest that DAMGO selectively hyperpolarizes NRM GABAergic neurons by opening inwardly rectifying K+ channels and that GRK2 mediates short‐term homologous desensitization of µ‐opioid receptors in NRM GABAergic neurons.

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