Contribution of adrenomedullin to the switch of G protein-coupled μ-opioid receptors from Gi to Gs in the spinal dorsal horn following chronic morphine exposure in rats.

<bold>Background and Purpose: </bold>Chronic exposure to morphine increases spinal adrenomedullin (AM) bioactivity resulting in the development and maintenance of morphine tolerance. This study investigated the possible involvement of AM in morphine-evoked alteration in μ-opioid receptor-coupled G proteins.<bold>Experimental Approach: </bold>Agents were administered intrathecally (i.t.) in rats. Nociceptive behaviours and cumulative dose-response of morphine analgesia were assessed. Neurochemicals in the spinal dorsal horn were assayed by immunoprecipitation, Western blot analysis and ELISA.<bold>Key Results: </bold>Intrathecal injection of AM (8 μg) for 9 days decreased and increased the levels of μ receptor-coupled Gi and Gs proteins respectively. Morphine stimulation (5 μg) after chronic treatment with AM also induced an increase in cAMP production in the spinal dorsal horn. Co-administration of the selective AM receptor antagonist AM22-52 inhibited chronic morphine-evoked switch of G protein-coupled μ receptor from Gi to Gs. Chronic exposure to AM increased the phosphorylation of cAMP-responsive element-binding protein (CREB) and ERK. Co-administration of the PKA inhibitor H-89 (5 μg) or MEK1 inhibitor PD98059 (1 μg) reversed the AM-induced thermal/mechanical hypersensitivity, decline in morphine analgesic potency, switch of G protein-coupled μ receptor and increase in cAMP.<bold>Conclusions and Implications: </bold>The present study supports the hypothesis that an increase in AM activity in the spinal dorsal horn contributes to the switch of the μ receptor-coupled G protein from Gi to Gs protein via the activation of cAMP/PKA/CREB and ERK signalling pathways in chronic morphine use. [ABSTRACT FROM AUTHOR]