μ-阿片类药物吗啡和丁丙诺啡对大鼠佐剂性关节炎发展的影响。
Effect of mu-opioids morphine and buprenorphine on the development of adjuvant arthritis in rats.
作者信息
Walker J S, Chandler A K, Wilson J L, Binder W, Day R O
机构信息
School of Physiology & Pharmacology, University of New South Wales, Sydney, Australia.
出版信息
Inflamm Res. 1996 Nov;45(11):557-63. doi: 10.1007/BF02342227.
OBJECTIVE AND DESIGN
On the basis that endogenous opioids play a role in the physiological response to inflammation, this study tests the anti-arthritic effects of a mu-opioid agonist, morphine and the partial mu-agonist, buprenorphine.
MATERIAL
Male Lewis rats were used.
TREATMENT
Rats were inoculated subcutaneously with 0.05 ml of Freund's complete adjuvant (5 mg/ml) into the right hind paw to produce adjuvant arthritis. Morphine (either 10 to 60 mg/kg/day s.c. bolus or 60 mg/kg/day s.c. infusion) and buprenorphine (0.65 +/- 0.06 mg/kg/day, orally), respectively, were administered for 3 days during the primary inflammatory phase of adjuvant arthritis.
METHODS
The progression of adjuvant arthritis was monitored every three days by body weight change and hind limb oedema (ipsilateral and contralateral). On day 21 the animals were sacrificed and histology and radiography of the contralateral limb were performed. In rats receiving Freund's adjuvant and no drug treatment, the incidence of arthritis was 89%. Effect was expressed as the pooled severity index (PSI) derived from the arithmetic average of the volume, histology and radiography scores in the contralateral hind limb.
RESULTS
Buprenorphine had no effect on experimental arthritis (PSI control vs treated: 242 +/- 28 vs 253 +/- 28%). In contrast, morphine by subcutaneous injection twice daily (10 to 60 mg/kg/day) but not by subcutaneous infusion (60 mg/kg/day) was found to attenuate the progression of adjuvant arthritis in a dose-dependent manner. This indicates that the anti-arthritic effects of morphine are opioid receptor mediated (ED50, 58 +/- 9 mg/kg) and suggests that the local concentration reached effective levels only after subcutaneous injection. It is also possible that the high doses of morphine were anti-inflammatory through effects at the kappa receptor. However, these high doses of morphine produced death in one third of the rats, the calculated lethal dose (LD50, 63 +/- 2 mg/kg) being close to the effective dose.
CONCLUSION
Anti-arthritic effects of morphine are opioid receptor mediated but morphine use for this indication is restricted by its adverse effects.
目的与设计
基于内源性阿片类物质在炎症生理反应中起作用，本研究测试了μ阿片受体激动剂吗啡和部分μ激动剂丁丙诺啡的抗关节炎作用。
材料
使用雄性Lewis大鼠。
处理
大鼠右后爪皮下接种0.05 ml弗氏完全佐剂（5 mg/ml）以诱发佐剂性关节炎。在佐剂性关节炎的原发性炎症期，分别给予吗啡（10至60 mg/kg/天皮下推注或60 mg/kg/天皮下输注）和丁丙诺啡（0.65±0.06 mg/kg/天，口服），持续3天。
方法
每三天通过体重变化和后肢水肿（同侧和对侧）监测佐剂性关节炎的进展。在第21天处死动物，并对侧肢体进行组织学和放射学检查。在接受弗氏佐剂且未进行药物治疗的大鼠中，关节炎发病率为89%。效应以从对侧后肢体积、组织学和放射学评分的算术平均值得出的综合严重程度指数（PSI）表示。
结果
丁丙诺啡对实验性关节炎无作用（PSI对照组与治疗组：242±28对253±28%）。相比之下，发现每日两次皮下注射吗啡（10至60 mg/kg/天）而非皮下输注（60 mg/kg/天）能以剂量依赖性方式减轻佐剂性关节炎的进展。这表明吗啡的抗关节炎作用是由阿片受体介导的（ED50，58±9 mg/kg），并提示仅皮下注射后局部浓度才达到有效水平。也有可能高剂量吗啡通过对κ受体的作用具有抗炎作用。然而，这些高剂量吗啡导致三分之一的大鼠死亡，计算得出的致死剂量（LD50，63±2 mg/kg）接近有效剂量。
结论
吗啡的抗关节炎作用是由阿片受体介导的，但吗啡用于该适应症受到其不良反应的限制。
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