Wang H-Y, Friedman E, Olmstead M C, Burns L H
Department of Physiology and Pharmacology, City University of New York Medical School, 138th Street and Convent Avenue, New York, NY 10031, USA.
Neuroscience. 2005;135(1):247-61. doi: 10.1016/j.neuroscience.2005.06.003.
Opiates produce analgesia by activating mu opioid receptor-linked inhibitory G protein signaling cascades and related ion channel interactions that suppress cellular activities by hyperpolarization. After chronic opiate exposure, an excitatory effect emerges contributing to analgesic tolerance and opioid-induced hyperalgesia. Ultra-low-dose opioid antagonist co-treatment blocks the excitatory effects of opiates in vitro, as well as opioid analgesic tolerance and dependence, as was demonstrated here with ultra-low-dose naloxone combined with morphine. While the molecular mechanism for the excitatory effects of opiates is unclear, a switch in the G protein coupling profile of the mu opioid receptor and adenylyl cyclase activation by Gbetagamma have both been suggested. Using CNS regions from rats chronically treated with vehicle, morphine, morphine+ultra-low-dose naloxone or ultra-low-dose naloxone alone, we examined whether altered mu opioid receptor coupling to G proteins or adenylyl cyclase activation by Gbetagamma occurs after chronic opioid treatment. In morphine-naïve rats, mu opioid receptors coupled to Go in striatum and to both Gi and Go in periaqueductal gray and spinal cord. Although chronic morphine decreased Gi/o coupling by mu opioid receptors, a pronounced coupling to Gs emerged coincident with a Gbetagamma interaction with adenylyl cyclase types II and IV. Co-treatment with ultra-low-dose naloxone attenuated both the chronic morphine-induced Gs coupling and the Gbetagamma signaling to adenylyl cyclase, while increasing Gi/o coupling toward or beyond vehicle control levels. These findings provide a molecular mechanism underpinning opioid tolerance and dependence and their attenuation by ultra-low-dose opioid antagonists.
阿片类药物通过激活与μ阿片受体相连的抑制性G蛋白信号级联反应以及相关离子通道相互作用来产生镇痛作用，这些相互作用通过超极化抑制细胞活动。长期接触阿片类药物后，会出现一种兴奋效应，导致镇痛耐受性和阿片类药物诱导的痛觉过敏。超低剂量阿片类拮抗剂联合治疗可在体外阻断阿片类药物的兴奋效应，以及阿片类镇痛耐受性和依赖性，正如本文用超低剂量纳洛酮联合吗啡所证明的那样。虽然阿片类药物兴奋效应的分子机制尚不清楚，但有人提出μ阿片受体的G蛋白偶联模式发生了转变，以及Gβγ激活腺苷酸环化酶。我们使用来自长期接受赋形剂、吗啡、吗啡+超低剂量纳洛酮或单独超低剂量纳洛酮治疗的大鼠的中枢神经系统区域，研究了慢性阿片类药物治疗后μ阿片受体与G蛋白的偶联或Gβγ对腺苷酸环化酶的激活是否发生改变。在未接触过吗啡的大鼠中，μ阿片受体在纹状体中与Go偶联，在导水管周围灰质和脊髓中与Gi和Go均偶联。虽然慢性吗啡降低了μ阿片受体与Gi/o的偶联，但与Gs的明显偶联出现，同时Gβγ与II型和IV型腺苷酸环化酶相互作用。超低剂量纳洛酮联合治疗减弱了慢性吗啡诱导的Gs偶联以及Gβγ向腺苷酸环化酶的信号传递，同时使Gi/o偶联增加至接近或超过赋形剂对照水平。这些发现为阿片类药物耐受性和依赖性及其被超低剂量阿片类拮抗剂减弱提供了分子机制。
