Differential mechanisms of morphine antinociceptive tolerance revealed in βarrestin-2 knock-out mice

LM Bohn, RJ Lefkowitz, MG Caron - Journal of Neuroscience, 2002 - Soc Neuroscience
Journal of Neuroscience, 2002Soc Neuroscience
Morphine induces antinociception by activating μ opioid receptors (μORs) in spinal and
supraspinal regions of the CNS. βarrestin-2 (βarr2), a G-protein-coupled receptor-regulating
protein, regulates the μOR in vivo. We have shown previously that mice lacking βarr2
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 βarr2-μOR interaction in other …
Morphine induces antinociception by activating μ opioid receptors (μORs) in spinal and supraspinal regions of the CNS. βarrestin-2 (βarr2), a G-protein-coupled receptor-regulating protein, regulates the μOR in vivo. We have shown previously that mice lacking βarr2 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 βarr2-μOR interaction in other neuronal systems, we have, in the present study, tested βarr2 knock-out (βarr2-KO) mice using the warm water tail-immersion paradigm, which primarily assesses spinal reflexes to painful thermal stimuli. In this test, the βarr2-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 βarr2-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 providein vivo evidence that the μOR is differentially regulated in diverse regions of the CNS. Furthermore, although βarr2 appears to be the most prominent and proximal determinant of μOR desensitization and morphine tolerance, in the absence of this mechanism, the contributions of a PKC-dependent regulatory system become readily apparent.
Soc Neuroscience