Contribution of adrenomedullin to the switch of G protein-coupled mu-opioid receptors from Gi to Gs in the spinal dorsal horn following chronic morphine exposure in rats
Contribution of adrenomedullin to the switch of G protein-coupled mu-opioid receptors from Gi to Gs in the spinal dorsal horn following chronic morphine exposure in rats
复制标题
大鼠慢性吗啡暴露后，肾上腺髓质素对脊髓背角 G 蛋白偶联 mu-阿片受体从 Gi 转变为 Gs 的贡献
DOI：
10.1111/bph.13419
复制
发表时间：
2016
影响因子：
7.3
通讯作者：
Hong Yanguo
中科院分区：
文献类型：
--
作者：
Wang Dongmei;Zeng Juan;Li Qi;Huang Jianzhong;Couture Rejean;Hong Yanguo
背景和目的：吗啡慢性暴露可增加脊髓肾上腺髓质素（AM）的生物活性，导致吗啡耐受的发生和维持。本研究调查了AM可能参与吗啡诱发的μ阿片受体偶联G蛋白的改变。对大鼠评估伤害性行为和吗啡镇痛的累积剂量反应。结果鞘内注射AM（8 μg）9 d后，脊髓背角μ受体偶联的Gi和Gs蛋白水平分别降低和升高。AM慢性处理后，吗啡刺激（5 μg）也诱导脊髓背角cAMP产生增加。选择性AM受体拮抗剂AM 22 - 52的联合给药可抑制吗啡慢性诱发的G蛋白偶联μ受体从GI到Gs的转换。慢性暴露于AM增加了cAMP反应元件结合蛋白（CREB）和ERK的磷酸化。PKA抑制剂H-89（5 μg）或MEK 1抑制剂PD 98059（1 μg）的联合给药逆转了AM诱导的热/机械超敏反应，吗啡镇痛效力下降，结论与意义本研究支持了脊髓背角AM活性的增加有助于μ受体偶联G蛋白的转换的假设在慢性吗啡使用中通过cAMP/PKA/CREB和ERK信号通路的激活从Gi到Gs蛋白。
Background and PurposeChronic 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 ApproachAgents 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 ResultsIntrathecal 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 AM22–52inhibited 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 ImplicationsThe 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.