目标:地佐辛和喷他佐辛,在中国广泛用于术后疼痛,最初被认为是针对μ阿片受体(MORs)和κ阿片受体(KORs)的混合激动剂/拮抗剂。然而,地佐辛通过MOR激活和去甲肾上腺素再摄取抑制(NRI)可缓解慢性神经性疼痛.这项研究调查了地佐辛和喷他佐辛诱导的抗伤害感受和身体依赖性的发展,与典型的MOR-NRI阿片类药物他喷他多相比。
方法:进行钙动员试验以评估药物的效力,同时进行热板试验以比较抗伤害感受。将身体依赖性的发展与吗啡进行了比较。
结果:地佐辛治疗,喷他佐辛和他汀多刺激HEK293细胞中的钙动员稳定表达MORs但不表达KORs,地佐辛和喷他佐辛抑制KOR活性。皮下注射地佐辛-,他汀多和喷他佐辛诱导的抗伤害感受剂量依赖性,在热板测试中。鞘内注射MOR拮抗剂CTAP,去甲肾上腺素耗竭6-OHDA和α2-肾上腺素受体(α2-AR)拮抗剂育亨宾部分拮抗地佐辛,喷他佐辛和他喷他多的镇痛作用。而特定的KOR拮抗剂GNTI并没有改变他们的镇痛感受,推定的反向KOR激动剂nor-BNI可降低地佐辛和喷他佐辛的镇痛作用。此外,CTAP和6-OHDA或育亨宾联合阻断地佐辛和他喷他多的抗伤害感受,但对喷他佐辛的抗伤害感受表现出与单用CTAP相同的部分抑制.此外,与吗啡和喷他佐辛相比,地佐辛和他他喷他多的长期治疗减少了与身体依赖相关的戒断症状,通过脊髓6-OHDA或育亨宾治疗恢复。
结论:我们的研究结果表明,地佐辛和他喷他多,但不是喷他佐辛,通过MOR激活和NRI的双重机制,在伤害性疼痛中发挥显着的抗伤害作用,而滥用责任较少。
OBJECTIVE: Dezocine and pentazocine, widely prescribed in China for postoperative pain, were initially considered as mixed agonist/antagonist targeting μ-opioid receptors (MORs) and κ-opioid receptors (KORs). However, dezocine has been revealed to alleviate chronic neuropathic pain through MOR activation and norepinephrine reuptake inhibition (NRI). This study investigated dezocine- and pentazocine-induced antinociception and physical dependence development, compared to the typical MOR-NRI opioid tapentadol.
METHODS: Calcium mobilization assay was conducted to assess the potency of the drugs while hot-plate test was performed to compare the antinociception. Physical dependence development was compared with morphine.
RESULTS: Treatment with dezocine, pentazocine and tapentadol stimulated calcium mobilization in HEK293 cells stably expressed MORs but not KORs, whereas dezocine and pentazocine inhibited KOR activities. Subcutaneously injected dezocine-, tapentadol- and pentazocine-induced antinociception dose-dependently, in hot-plate test. Intrathecally injected MOR antagonist CTAP, norepinephrine depletor 6-OHDA and α2-adrenoceptor (α2-AR) antagonist yohimbine partially antagonized dezocine, pentazocine and tapentadol antinociception. Whereas specific KOR antagonist GNTI did not alter their antinociception, the putative inverse KOR agonist nor-BNI reduced dezocine and pentazocine antinociception. Moreover, combined CTAP and 6-OHDA or yohimbine blocked dezocine and tapentadol antinociception but displayed the same partial inhibition on pentazocine antinociception as CTAP alone. Furthermore, compared to morphine and pentazocine, long-term treatment with dezocine and tapentadol produced much less physical dependence-related withdrawal signs, which were restored by spinal 6-OHDA or yohimbine treatment.
CONCLUSIONS: Our findings illustrated that dezocine and tapentadol, but not pentazocine, exert remarkable antinociception in nociceptive pain with less abuse liability via dual mechanisms of MOR activation and NRI.