Antagonism of the mu-delta opioid receptor heterodimer enhances opioid antinociception by activating Src and calcium/calmodulin-dependent protein kinase II signaling.
Antagonism of the mu-delta opioid receptor heterodimer enhances opioid antinociception by activating Src and calcium/calmodulin-dependent protein kinase II signaling.
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DOI：
10.1097/j.pain.0000000000002320
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发表时间：
2022-01-01
期刊：
影响因子：
7.4
通讯作者：
Streicher JM
中科院分区：
文献类型：
--
作者：
Keresztes A;Olson K;Nguyen P;Lopez-Pier MA;Hecksel R;Barker NK;Liu Z;Hruby V;Konhilas J;Langlais PR;Streicher JM
阿片受体是疼痛、奖励和成瘾的重要调节因子。有限的证据表明，mu和delta阿片受体形成异源二聚体（MDOR），可能在阿片诱导的镇痛中起负反馈制动作用。然而，体内MDOR的证据是间接的和有限的，并且很少有选择性的工具可用。我们最近发表了第一个MDOR选择性拮抗剂D24M，使我们能够测试MDOR在小鼠中的作用。因此，我们将D24M和阿片类药物联合治疗CD-1小鼠，用于甩尾、爪切口和化疗诱导的周围神经病变疼痛模型。D24M治疗可使氧吗啡酮抗伤害性提高54.7% ~ 628%。这种增强不能被mu和delta选择性拮抗剂CTAP、纳曲多和纳洛唑嗪复制，D24M在Rotarod试验中有轻微的短暂效应，表明这种增加对MDOR是选择性的。然而，D24M对吗啡或丁丙诺啡没有影响，这表明只有特定的阿片类药物与MDOR相互作用。为了找到其中的机制，我们对小鼠脑干进行了磷蛋白质组学分析。我们发现Src和CaMKII激酶被oxymorphone抑制，D24M使其恢复。我们能够证实Src和CaMKII在使用小分子抑制剂（KN93, Src- i1）增强d24m抗伤害感受中的作用。总之，这些结果提供了直接的体内证据，表明MDOR通过抑制Src和CaMKII信号转导而起到阿片负反馈制动器的作用。这些结果进一步表明，MDOR拮抗剂可能是改善临床阿片类药物治疗的一种手段。
The opioid receptors are important regulators of pain, reward, and addiction. Limited evidence suggests the mu and delta opioid receptors form a heterodimer (MDOR), which may act as a negative feedback brake on opioid-induced analgesia. However, evidence for the MDOR in vivo is indirect and limited, and there are few selective tools available. We recently published the first MDOR-selective antagonist, D24M, allowing us to test the role of the MDOR in mice. We thus co-treated CD-1 mice with D24M and opioids in tail flick, paw incision, and chemotherapy-induced peripheral neuropathy pain models. D24M treatment enhanced oxymorphone anti-nociception in all models by 54.7%−628%. This enhancement could not be replicated with the mu and delta selective antagonists CTAP, naltrindole, and naloxonazine, and D24M had a mild transient effect in the Rotarod test, suggesting this increase is selective to the MDOR. However, D24M had no effect on morphine or buprenorphine, suggesting that only specific opioids interact with the MDOR. To find a mechanism we performed phosphoproteomic analysis on brainstems of mice. We found that the kinases Src and CaMKII were repressed by oxymorphone, which was restored by D24M. We were able to confirm the role of Src and CaMKII in D24M-enhanced anti-nociception using small molecule inhibitors (KN93, Src-I1). Together these results provide direct in vivo evidence that the MDOR acts as an opioid negative feedback brake, which occurs via the repression of Src and CaMKII signal transduction. These results further suggest that MDOR antagonism could be a means to improve clinical opioid therapy.
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影响因子：
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