Abstract
Morphine induces antinociception by activating mu opioid receptors (muORs) in spinal and supraspinal regions of the CNS. (Beta)arrestin-2 (beta)arr2), a G-protein-coupled receptor-regulating protein, regulates the muOR in vivo. We have shown previously that mice lacking (beta)arr2 experience enhanced morphine-induced analgesia and do not become tolerant to morphine as determined in the hot-plate test, a paradigm that primarily assesses supraspinal pain responsiveness. To determine the general applicability of the (beta)arr2-muOR interaction in other neuronal systems, we have, in the present study, tested (beta)arr2 knock-out ((beta)arr2-KO) mice using the warm water tail-immersion paradigm, which primarily assesses spinal reflexes to painful thermal stimuli. In this test, the (beta)arr2-KO mice have greater basal nociceptive thresholds and markedly enhanced sensitivity to morphine. Interestingly, however, after a delayed onset, they do ultimately develop morphine tolerance, although to a lesser degree than the wild-type (WT) controls. In the (beta)arr2-KO but not WT mice, morphine tolerance can be completely reversed with a low dose of the classical protein kinase C (PKC) inhibitor chelerythrine. These findings provide in vivo evidence that the muOR is differentially regulated in diverse regions of the CNS. Furthermore, although (beta)arr2 appears to be the most prominent and proximal determinant of muOR desensitization and morphine tolerance, in the absence of this mechanism, the contributions of a PKC-dependent regulatory system become readily apparent.
Highlights
Morphine induces antinociception by activating opioid receptors (ORs) in spinal and supraspinal regions of the CNS. arrestin-2 (arr2), a G-protein-coupled receptor-regulating protein, regulates the OR in vivo
Desensitization occurs when agonist-stimulated receptor is phosphorylated by a G-protein-coupled receptor (GPCR) kinase (GRK) and attracts an arrestin protein (Ferguson et al, 1998; Krupnick and Benovic, 1998; Lefkowitz, 1998)
Several reports have demonstrated the importance of GRKs and arrestins in determining GPCR signaling in cell cultures, where it has been shown that certain GRKs and arrestins can affect GPCR desensitization
Summary
Morphine induces antinociception by activating opioid receptors (ORs) in spinal and supraspinal regions of the CNS. arrestin-2 (arr2), a G-protein-coupled receptor-regulating protein, regulates the OR in vivo. In the arr2-KO but not WT mice, morphine tolerance can be completely reversed with a low dose of the classical protein kinase C (PKC) inhibitor chelerythrine These findings provide in vivo evidence that the OR is differentially regulated in diverse regions of the CNS. By using mice that lack an essential component of the desensitization process, arr, we are able to assess the contribution of this and other mechanisms to the antinociceptive actions of morphine in various pain perception paradigms. It is becoming increasingly apparent that the regulation of a particular receptor may differ depending on its cellular environment, be it different regions of the nervous system or within different cell types Using this model, we demonstrate that the spinal antinociceptive actions of morphine are regulated by arr2- and PKC-dependent pathways, suggesting that, within the spinal system, both of these regulatory mechanisms contribute to OR regulation
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