Involvement of spinal G-protein inwardly rectifying potassium (GIRK) channels in the enhanced antinociceptive effects of the activation of both μ-opioid and cannabinoid CB1 receptors.
Involvement of spinal G-protein inwardly rectifying potassium (GIRK) channels in the enhanced antinociceptive effects of the activation of both μ-opioid and cannabinoid CB1 receptors.
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脊髓 G 蛋白内向整流钾 (GIRK) 通道参与 μ-阿片类药物和大麻素 CB1 受体激活增强的抗伤害感受作用。
DOI：
10.1016/j.jphs.2022.04.002
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Y.
中科院分区：
文献类型：
--
作者：
Takemura;Y.;Sudo;Y.;Saeki;T.;Kurata;S.;Suzuki;T.;Mori;T.;Uezono;Y.
神经性疼痛对阿片类镇痛药是难治性的。由于μ-阿片受体（MOR）和大麻素受体（CBR）之间存在功能上的联系，本研究旨在通过G蛋白偶联向内纠偏钾通道（GIRKs）介导的神经性疼痛的抗伤害性作用来研究MOR和CB1R之间的相互作用。在有或没有部分坐骨神经结扎的小鼠中，评估了MOR和CBR激动剂对假性感觉反应或神经性疼痛的抗感觉作用。为了研究MOR与CB1R之间的功能相互作用，我们采用双电极电压钳法对小鼠脊髓卵母细胞进行了GIRK电生理记录，并进行了Western blotting。MOR激动剂DAMGO和CB1R激动剂CP55,940联合给药增强了共表达MOR、CB1R和GIRK1/2的异种卵母细胞的内整流K+电流。此外，吗啡和CBR激动剂WIN-55,212-2联合使用，以一种抑制-可逆的方式产生显著的抗感觉性作用。此外，CB1R在脊髓神经性疼痛下上调，并且吗啡加WIN-55,212-2重复治疗不改变这种上调和抗感觉性作用。我们的研究结果表明，MOR和CBR激动剂联合使用可以通过小鼠脊髓中的GIRK1增强它们的抗伤害感受作用。
Neuropathic pain is refractory to opioid analgesics. Since there are functional linkages between μ-opioid receptors (MOR) and cannabinoid receptors (CBR), the present study was designed to investigate the interactions between MOR and CB1R based on antinociceptive effects for neuropathic pain mediated through G protein-coupled inwardly-rectifying potassium channels (GIRKs). The antinociceptive effects against pseudonociceptive response or neuropathic pain of MOR and CBR agonists were assessed in mice with or without partial sciatic nerve ligation. To investigate the functional interaction between MOR and CB1R, electrophysiological recording through GIRK was performed using the two-electrode voltage-clamp method in oocytes along with Western blotting in the spinal cord of mice. Co-administration of the MOR agonist DAMGO and the CB1R agonist CP55,940 augmented inwardly rectifying K+currents inXenopusoocytes co-expressing MOR, CB1R and GIRK1/2. Further, combination of morphine and the CBR agonist WIN-55,212-2 produced prominent antinociceptive effects in an i.t. GIRK1 inhibitor-reversible manner. Furthermore, CB1R was upregulated under neuropathic pain in the spinal cord, and such upregulation and antinociceptive effects were not altered by repeated treatment with morphine plus WIN-55,212-2. Our findings suggest that co-administration of MOR and CBR agonists could enhance their antinociceptive effects through GIRK1 in the spinal cord of mice.