将大麻素WIN 55,212-2持续输注到周围神经损伤部位可减轻机械性和冷超敏反应。
Continuous infusion of the cannabinoid WIN 55,212-2 to the site of a peripheral nerve injury reduces mechanical and cold hypersensitivity.
作者信息
Lever I J, Pheby T M, Rice A S C
机构信息
Department of Anaesthetics, Intensive Care and Pain Medicine, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital Campus, London, UK.
出版信息
Br J Pharmacol. 2007 May;151(2):292-302. doi: 10.1038/sj.bjp.0707210. Epub 2007 Mar 20.
BACKGROUND AND PURPOSE
Cannabinoids have analgesic and anti-inflammatory properties but their use is limited by psychotropic activity at CNS receptors. Restricting cannabinoid delivery to peripheral tissues at systemically inactive doses offers a potential solution to this problem.
EXPERIMENTAL APPROACH
WIN 55,212-2 was continuously delivered to the site of a partial ligation injury to the sciatic nerve via a perineural catheter connected to a mini-osmotic pump implanted at the time of injury. Bilateral reflex limb withdrawal behaviour was measured in adult male Wistar rats in response to mechanical and cooling stimulation of the hind paw.
KEY RESULTS
Compared with vehicle treatment, WIN 55,212-2 (1.4 microg microl(-1) hr(-1)) reduced hypersensitivity to stimuli applied to the injured limb at 2, 4 and 6 days after injury. The effects of WIN 55,212-2 (0.6-2.8 microg microl(-1) hr(-1)) were dose-dependent. Estimated EC(50) values for reduction in mean responses to mechanical and cooling stimulation (day 4 post-surgery) were 1.55 (95% C.I, [1.11-2.16]) microg microl(-1) hr(-1) and 1.52 (95% C.I, [1.07-2.18]) microg microl(-1) hr(-1), respectively. When delivered to the contralateral side to injury, WIN 55,212-2 (1.4 or 2.8 microg microl(-1) hr(-1)) did not significantly affect nerve injury-associated hypersensitivity. Co-perineural application of a CB(1) receptor antagonist SR141716a and WIN 55,212-2 prevented the effects of WIN 55,212-2 on hypersensitivity. Co-application of CB(2) receptor antagonist SR144528 reversed WIN 55,212-2's effect on mechanical hypersensitivity on day 2 only.
CONCLUSIONS AND IMPLICATIONS
These data support a peripheral antihyperalgesic effect of WIN 55,212-2 when delivered directly to the site of a nerve injury at systemically inactive doses.
背景与目的
大麻素具有镇痛和抗炎特性，但其应用因对中枢神经系统（CNS）受体的精神活性作用而受到限制。以全身无活性剂量将大麻素递送至外周组织为解决这一问题提供了一种潜在方案。
实验方法
通过在损伤时植入的连接微型渗透泵的神经周围导管，将WIN 55,212-2持续递送至坐骨神经部分结扎损伤部位。在成年雄性Wistar大鼠中，测量双侧反射性肢体退缩行为，以响应后爪的机械和冷刺激。
主要结果
与赋形剂处理相比，WIN 55,212-2（1.4微克微升⁻¹小时⁻¹）在损伤后第2、4和6天降低了对施加于损伤肢体的刺激的超敏反应。WIN 55,212-2（0.6 - 2.8微克微升⁻¹小时⁻¹）的作用呈剂量依赖性。对机械和冷刺激平均反应降低（术后第4天）的估计半数有效浓度（EC₅₀）值分别为1.55（95%置信区间，[1.11 - 2.16]）微克微升⁻¹小时⁻¹和1.52（95%置信区间，[1.07 - 2.18]）微克微升⁻¹小时⁻¹。当递送至损伤对侧时，WIN 55,212-2（1.4或2.8微克微升⁻¹小时⁻¹）对神经损伤相关的超敏反应无显著影响。CB₁受体拮抗剂SR141716a与WIN 55,212-2联合神经周围应用可预防WIN 55,212-2对超敏反应的作用。CB₂受体拮抗剂SR144528联合应用仅在第2天逆转了WIN 55,212-2对机械性超敏反应的作用。
结论与意义
这些数据支持当以全身无活性剂量直接递送至神经损伤部位时，WIN 55,212-2具有外周抗痛觉过敏作用。
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