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The Journal of Neuroscience, September 10, 2003, 23(23):8360-8369

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Brain Region-Specific Mechanisms for Acute Morphine-Induced Mitogen-Activated Protein Kinase Modulation and Distinct Patterns of Activation during Analgesic Tolerance and Locomotor Sensitization

Shoshana Eitan,¹ Camron D. Bryant,^1,2 Nazli Saliminejad,¹ Yu C. Yang,¹ Elroy Vojdani,¹ Duane Keith, Jr,¹ Roberto Polakiewicz,³ and Christopher J. Evans¹

¹Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Neuropsychiatric Institute, and ²Interdepartmental Program in Neuroscience, University of California, Los Angeles, Los Angeles, California 90024, and ³Cell Signaling Technology, Beverly, Massachusetts 01915

Opioid-receptor activation in cell lines results in phosphorylation of p42/44 mitogen-activated protein kinase (MAPK), which contributes to agonist-induced desensitization of adenylate cyclase signaling. In this study, morphine-induced MAPK modulation was examined in the mouse brain using antibodies against phosphorylated MAPK. Thirty minutes after systemic morphine, MAPK modulation was observed in brain areas associated with analgesia and reward. Activation of MAPK was increased in the anterior cingulate (Acc), somato-sensory and association cortices, and locus ceruleus (LC). In contrast, MAPK activation was decreased in the nucleus accumbens and central amygdala (CeA). Double-label confocal microscopy revealed that morphine-induced MAPK modulation occurred predominantly in cells not expressing µ-opioid receptors, with the exception of the LC. Furthermore, the NMDA receptor antagonist 3,3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonate blocked morphine-induced MAPK modulation in several cortical areas including the Acc. We then examined morphine-induced MAPK modulation during expression of either analgesic tolerance or locomotor sensitization, which were differentiated by two repeated morphine regimens. Analgesic tolerance was accompanied by tolerance to morphine-induced MAPK modulation in all of the brain areas examined except the CeA. Locomotor sensitization resulted in sensitization to morphine-induced MAPK activation in the posterior basolateral amygdala. Additionally, a pronounced instatement of morphine-induced MAPK activation was observed in CA3 hippocampal processes. This instatement was observed during expression of tolerance; however, it was not significant during sensitization. In summary, these results provide distinct, region-specific mechanisms for morphine-induced MAPK modulation in the mouse brain and give insight into the brain circuitry involved in acute and adaptive opioid behaviors.

Key words: antinociception; reward; opioid; extracellular-regulated kinase (ERK)1/2; hot plate; opioid signaling; NMDA; µ

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Received March 28, 2003; revised July 11, 2003; accepted July 16, 2003.

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