Supersensitivity to μ-opioid receptor-mediated inhibition of the adenylyl cyclase pathway involves pertussis toxin-resistant Gα protein subunits

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• 作者：Ricardo Mostany ; Á ; lvaro D&#xed ; az ; Elsa M. Valdiz&#xe1 ; n ; Mar&#xed ; a Rodr&#xed ; guez-Mu&#xf1 ; oz ; Javier Garz&#xf3 ; n ; Mar&#xed ; a A. Hurl&#xe9
• 关键词：Nociception ; Analgesia ; Opioid tolerance ; Opioid supersensitivity ; G-protein ; Adenylyl cyclase ; μ ; -Opioids ; Calcium antagonist
• 刊名：Neuropharmacology
• 出版年：2008
• 期刊代码：33_00283908
• 类别：pha
• 出版时间：May 2008
• 卷：54
• 期：6
• 页码：989-997
• 文件大小：672 K

摘要

Sustained administration of opioids leads to antinociceptive tolerance, while prolonged association of L-type Ca²⁺ channel blockers (e.g. nimodipine) with opioids results in increased antinociceptive response. Herein, we investigated the changes in μ-opioid receptor signalling underlying this shift from analgesic tolerance to supersensitivity. Thus, the interaction of μ-opioid receptors with G proteins and adenylyl cyclase was examined in lumbar spinal cord segments of rats. In control animals, the μ-opioid selective agonists, sufentanil and DAMGO, stimulated [³⁵S]5′-(gamma-thio)-triphosphate ([³⁵S]GTPγS) binding and inhibited forskolin-stimulated adenylyl cyclase activity, through a mechanism involving pertussis toxin (PTX) sensitive Gf" alt="greek small letter alpha" title="greek small letter alpha" border="0">_i/o subunits. Seven days of chronic sufentanil treatment developed antinociceptive tolerance associated with a reduction in μ-agonist-induced [³⁵S]GTPγS binding, μ-agonist-induced adenylyl cyclase inhibition, and co-precipitation of Gf" alt="greek small letter alpha" title="greek small letter alpha" border="0">_o, Gf" alt="greek small letter alpha" title="greek small letter alpha" border="0">_i2 Gf" alt="greek small letter alpha" title="greek small letter alpha" border="0">_z and Gf" alt="greek small letter alpha" title="greek small letter alpha" border="0">_q11 subunits with μ-opioid receptors. In contrast, combined nimodipine treatment with sufentanil over the same period increased the sufentanil analgesic response. This antinociceptive supersensitivity was accompanied by a significant increase of μ-agonist-induced inhibition of adenylyl cyclase that was resistant to the antagonism by PTX. In good agreement, co-precipitation of the PTX-resistant, Gf" alt="greek small letter alpha" title="greek small letter alpha" border="0">_z and Gf" alt="greek small letter alpha" title="greek small letter alpha" border="0">_q/11 subunits with μ-opioid receptors was not lowered. On the other hand, the PTX-sensitive subunits, Gf" alt="greek small letter alpha" title="greek small letter alpha" border="0">_i2 and Gf" alt="greek small letter alpha" title="greek small letter alpha" border="0">_o, as well as agonist-stimulated [³⁵S]GTPγS binding were still reduced. Our results demonstrate that μ-opioid analgesic tolerance follows uncoupling of spinal μ-opioid receptors from their G proteins and linked effector pathways. Conversely, the enhanced analgesic response following combined nimodipine treatment with sufentanil is associated with adenylyl cyclase supersensitivity to the opioid inhibitory effect through a mechanism involving PTX-resistant G protein subunits.