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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
Author(s) -
Wang Dongmei,
Zeng Juan,
Li Qi,
Huang Jianzhong,
Couture Réjean,
Hong Yanguo
Publication year - 2016
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13419
Subject(s) - creb , morphine , opioid , opioid receptor , receptor , pharmacology , nociception , mapk/erk pathway , chemistry , endocrinology , receptor antagonist , adrenomedullin , μ opioid receptor , medicine , stimulation , (+) naloxone , antagonist , phosphorylation , biochemistry , transcription factor , gene
Background and Purpose 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. Experimental Approach 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. Key Results 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 AM 22–52 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. Conclusions and Implications 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.