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The Journal of Neuroscience, December 1, 2002, 22(23):10494-10500

Differential Mechanisms of Morphine Antinociceptive Tolerance Revealed in Arrestin-2 Knock-Out Mice

Laura M. Bohn¹, Robert J. Lefkowitz², and Marc G. Caron¹

Howard Hughes Medical Institute Laboratories, Departments of ¹ Cell Biology and ² Biochemistry and Medicine, Duke University Medical Center, Durham, North Carolina 27710

Morphine induces antinociception by activating µ opioid receptors (µORs) in spinal and supraspinal regions of the CNS. arrestin-2 (arr2), a G-protein-coupled receptor-regulating protein, regulates the µOR in vivo. We have shown previously that mice lacking 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 arr2-µOR interaction in other neuronal systems, we have, in the present study, tested arr2 knock-out (arr2-KO) mice using the warm water tail-immersion paradigm, which primarily assesses spinal reflexes to painful thermal stimuli. In this test, the 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 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 µOR is differentially regulated in diverse regions of the CNS. Furthermore, although arr2 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.

Key words: morphine; µ opioid receptor; MOP; knock-out mice; arrestin; desensitization; G-protein-coupled receptors; tolerance; antinociception

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Copyright © 2002 Society for Neuroscience  0270-6474/02/222310494-07$05.00/0

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