Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, United States of America.
Depomed, Inc., Newark, CA, United States of America.
PLoS One. 2019 Jun 6;14(6):e0217371. doi: 10.1371/journal.pone.0217371. eCollection 2019.
Most clinically used opioids are thought to induce analgesia through activation of the mu opioid receptor (MOR). However, disparities have been observed between the efficacy of opioids in activating the MOR in vitro and in inducing analgesia in vivo. In addition, some clinically used opioids do not produce cross-tolerance with each other, and desensitization produced in vitro does not match tolerance produced in vivo. These disparities suggest that some opioids could be acting through other targets in vivo, but this has not been comprehensively tested. We thus screened 9 clinically relevant opioids (buprenorphine, hydrocodone, hydromorphone, morphine, O-desmethyl-tramadol, oxycodone, oxymorphone, tapentadol, tramadol) against 9 pain-related receptor targets (MOR, delta opioid receptor [DOR], kappa opioid receptor [KOR], nociceptin receptor [NOP], cannabinoid receptor type 1 [CB1], sigma-1 receptor [σ1R], and the monoamine transporters [NET/SERT/DAT]) expressed in cells using radioligand binding and functional activity assays. We found several novel interactions, including monoamine transporter activation by buprenorphine and σ1R binding by hydrocodone and tapentadol. Tail flick anti-nociception experiments with CD-1 mice demonstrated that the monoamine transporter inhibitor duloxetine selectively promoted buprenorphine anti-nociception while producing no effects by itself or in combination with the most MOR-selective drug oxymorphone, providing evidence that these novel interactions could be relevant in vivo. Our findings provide a comprehensive picture of the receptor interaction profiles of clinically relevant opioids, which has not previously been performed. Our findings also suggest novel receptor interactions for future investigation that could explain some of the disparities observed between opioid performance in vitro and in vivo.
大多数临床上使用的阿片类药物被认为通过激活μ阿片受体（MOR）来诱导镇痛。然而，在体外激活 MOR 的阿片类药物的功效和体内诱导镇痛的功效之间观察到了差异。此外，一些临床上使用的阿片类药物彼此之间不会产生交叉耐受，并且体外产生的脱敏与体内产生的耐受不匹配。这些差异表明，一些阿片类药物可能在体内通过其他靶点起作用，但这尚未得到全面测试。因此，我们使用放射性配体结合和功能活性测定法，针对 9 种与疼痛相关的受体靶标（MOR、δ阿片受体[DOR]、κ阿片受体[KOR]、孤啡肽受体[NOP]、大麻素受体 1 [CB1]、σ1 受体[σ1R]和单胺转运体[NET/SERT/DAT]）筛选了 9 种临床相关的阿片类药物（丁丙诺啡、氢可酮、氢吗啡酮、吗啡、O-去甲曲马多、羟考酮、羟吗啡酮、他喷他多、曲马多）。我们发现了几种新的相互作用，包括丁丙诺啡激活单胺转运体和氢可酮和他喷他多结合σ1R。用 CD-1 小鼠进行的尾巴拍打抗伤害实验表明，单胺转运体抑制剂度洛西汀选择性地促进丁丙诺啡的抗伤害作用，而自身或与最 MOR 选择性药物羟吗啡酮联合使用时没有作用，这提供了证据表明这些新的相互作用可能在体内相关。我们的研究结果提供了临床上相关阿片类药物受体相互作用谱的全面描述，这是以前没有进行过的。我们的研究结果还表明，对于未来的研究，可以探索新的受体相互作用，这些相互作用可能可以解释一些在体外和体内观察到的阿片类药物表现之间的差异。
