School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
Life Sci. 2021 Nov 15;285:119996. doi: 10.1016/j.lfs.2021.119996. Epub 2021 Sep 28.
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.
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.
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 α-adrenoceptor (α-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.
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.
地佐辛和喷他佐辛在中国被广泛用于术后疼痛治疗，最初被认为是同时靶向μ阿片受体（MORs）和κ阿片受体（KORs）的混合激动剂/拮抗剂。然而，地佐辛已被证明通过 MOR 激活和去甲肾上腺素再摄取抑制（NRI）来缓解慢性神经病理性疼痛。本研究比较了地佐辛和喷他佐辛与典型的 MOR-NRI 阿片类药物他喷他多的镇痛作用和躯体依赖的发展。
通过钙动员测定来评估药物的效力，通过热板试验比较镇痛作用。通过与吗啡比较来研究躯体依赖的发展。
地佐辛、喷他佐辛和他喷他多处理刺激稳定表达 MORs 的 HEK293 细胞中的钙动员，但不刺激 KORs，而地佐辛和喷他佐辛抑制 KOR 活性。皮下注射地佐辛、他喷他多和喷他佐辛剂量依赖性地诱导热板试验中的镇痛作用。鞘内注射 MOR 拮抗剂 CTAP、去甲肾上腺素耗竭剂 6-OHDA 和 α-肾上腺素能受体（α-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。而特异性 KOR 拮抗剂 GNTI 不改变它们的镇痛作用，假定的 KOR 反向激动剂 nor-BNI 降低地佐辛和喷他佐辛的镇痛作用。此外，联合 CTAP 和 6-OHDA 或育亨宾阻断地佐辛和他喷他多的镇痛作用，但与 CTAP 单独阻断时相比，对喷他佐辛的镇痛作用只有部分抑制。此外，与吗啡和喷他佐辛相比，长期使用地佐辛和他喷他多产生的躯体依赖相关戒断症状较少，这些症状可通过脊髓内 6-OHDA 或育亨宾治疗恢复。
我们的研究结果表明，地佐辛和他喷他多，而不是喷他佐辛，通过 MOR 激活和 NRI 的双重机制，在疼痛性疼痛中发挥显著的镇痛作用，且滥用潜力较小。
