King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, 200240, China.
Eur J Pharmacol. 2020 Jun 5;876:173062. doi: 10.1016/j.ejphar.2020.173062. Epub 2020 Mar 12.
Dezocine is an opioid analgesic widely used in China, occupying over 45% of the domestic market of opioid analgesics. We have recently demonstrated that dezocine produced mechanical antiallodynia and thermal antihyperalgesia through spinal μ-opioid receptor activation and norepinephrine reuptake inhibition in neuropathic pain. This study further explored the dual μ-opioid receptor and norepinephrine reuptake mechanisms underlying dezocine-induced mechanical antiallodynia in bone cancer pain, compared with tapentadol, the first recognized analgesic in this class. Dezocine and tapentadol, given subcutaneously, exerted profound mechanical antiallodynia in bone cancer pain rats in a dose-dependent manner, yielding similar maximal effects but different potencies: EDs of 0.6 mg/kg for dezocine and 7.5 mg/kg for tapentadol, respectively. Furthermore, their mechanical antiallodynia was partially blocked by intrathecal injection of the specific μ-opioid receptor antagonist CTAP, but not κ-opioid receptor antagonists GNTI and nor-BNI or δ-opioid receptor antagonist naltrindole. Intrathecal administrations of the specific norepinephrine depletor 6-OHDA (but not the serotonin depletor PCPA) for three consecutive days and single injection of the α-adrenoceptor antagonist phentolamine/α2-adrenoceptor antagonist yohimbine partially blocked dezocine- and tapentadol-induced mechanical antiallodynia. Strikingly, the combination of CTAP and yohimbine nearly completely blocked dezocine- and tapentadol-induced mechanical antiallodynia. Our results illustrate that both dezocine and tapentadol exert mechanical antiallodynia in bone cancer pain through dual mechanisms of μ-opioid receptor activation and norepinephrine reuptake inhibition, and suggest that the μ-opioid receptor and norepinephrine reuptake dual-targeting opioids are effective analgesics in cancer pain.
地佐辛是一种在中国广泛使用的阿片类镇痛药，占据了国内阿片类镇痛药市场的 45%以上。我们最近的研究表明，地佐辛通过激活脊髓 μ 阿片受体和抑制去甲肾上腺素再摄取，对神经病理性疼痛产生了机械性抗痛觉过敏和热痛觉过敏。本研究进一步探讨了地佐辛在骨癌痛中产生机械性抗痛觉过敏的双重 μ 阿片受体和去甲肾上腺素再摄取机制，与同类中首个被认可的镇痛药他喷他多进行了比较。地佐辛和他喷他多皮下给药，以剂量依赖的方式在骨癌痛大鼠中产生了明显的机械性抗痛觉过敏，产生了相似的最大效应，但效力不同：地佐辛的 ED 为 0.6mg/kg，他喷他多的 ED 为 7.5mg/kg。此外，它们的机械性抗痛觉过敏部分被鞘内注射特异性 μ 阿片受体拮抗剂 CTAP 阻断，但 κ 阿片受体拮抗剂 GNTI 和 nor-BNI 或 δ 阿片受体拮抗剂纳曲酮不阻断。连续三天鞘内给予特异性去甲肾上腺素耗竭剂 6-OHDA（而非 5-羟色胺耗竭剂 PCPA），单次注射 α-肾上腺素受体拮抗剂酚妥拉明/α2-肾上腺素受体拮抗剂育亨宾，部分阻断了地佐辛和他喷他多引起的机械性抗痛觉过敏。引人注目的是，CTAP 和育亨宾的联合应用几乎完全阻断了地佐辛和他喷他多引起的机械性抗痛觉过敏。我们的结果表明，地佐辛和他喷他多在骨癌痛中均通过 μ 阿片受体激活和去甲肾上腺素再摄取抑制的双重机制发挥机械性抗痛觉过敏作用，并提示 μ 阿片受体和去甲肾上腺素再摄取双重靶向阿片类药物是有效的癌痛治疗药物。
