Mansikka Heikki, Zhao Chengshui, Sheth Rishi N, Sora Ichiro, Uhl George, Raja Srinivasa N
Department of Anesthesiology and Critical Care Medicine, Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Anesthesiology. 2004 Apr;100(4):912-21. doi: 10.1097/00000542-200404000-00022.
Mice lacking the mu-opioid receptor gene have been used to characterize the role of mu-opioid receptors in nociception and the analgesic actions of opioid agonists. In this study, the authors determined the role of mu-opioid receptors in neuropathic pain behaviors and the effectiveness of mu- and kappa-opioid receptor agonists on this behavior in mice.
The authors studied the behavioral responses of mu-opioid receptor knockout and wild-type mice to thermal and mechanical stimuli before and after neuropathic pain induced by unilateral ligation and section of the L5 spinal nerve. Response to mechanical stimuli was evaluated by determining the frequency of hind paw withdrawal to repetitive stimulation using a series of von Frey monofilaments. Thermal hyperalgesia was assessed by determining the paw withdrawal latencies to radiant heat and frequency of hind paw withdrawal to cooling stimuli. The effects of systemic morphine, the kappa-opioid agonist U50488H, and naloxone on responses to mechanical and thermal stimuli were also studied in spinal nerve-injured mice.
After spinal nerve injury, wild-type mice developed increased responsiveness to mechanical, heat, and cooling stimuli ipsilateral to nerve injury. mu-Opioid receptor knockout mice not only had more prominent mechanical allodynia in the nerve-injured paw, but also expressed contralateral allodynia to mechanical stimuli. Hyperalgesia to thermal stimuli was similar between mu-opioid knockout and wild-type animals. Morphine decreased mechanical allodynia dose dependently (3-30 mg/kg subcutaneous) in wild-type mice--an effect that was attenuated in the heterozygous mice and absent in the homozygous mu-opioid knockout mice. The kappa-opioid agonist U50488H (3-10 mg/kg subcutaneous) attenuated mechanical allodynia in wild-type, heterozygous, and homozygous mu-opioid mice. Naloxone in wild-type mice resulted in enhanced ipsilateral and contralateral allodynia to mechanical stimuli that resembled the pain behavior observed in mu-opioid receptor knockout mice.
The authors' observations indicate that (1) unilateral nerve injury induces a bilateral tonic activation of endogenous mu-opioid receptor-mediated inhibition that attenuates mechanical allodynia but not thermal hyperalgesia, (2) both mu- and kappa-opioid agonists attenuate neuropathic pain in mice, and (3) the antihyperalgesic actions of morphine are mediated primarily via mu-opioid receptors.
缺乏μ-阿片受体基因的小鼠已被用于确定μ-阿片受体在伤害感受以及阿片类激动剂镇痛作用中的角色。在本研究中，作者确定了μ-阿片受体在神经性疼痛行为中的作用，以及μ-和κ-阿片受体激动剂对小鼠这种行为的有效性。
作者研究了μ-阿片受体基因敲除小鼠和野生型小鼠在单侧结扎并切断L5脊神经诱导神经性疼痛前后对热刺激和机械刺激的行为反应。通过使用一系列von Frey细丝确定后爪对重复刺激的撤回频率来评估对机械刺激的反应。通过确定对辐射热的爪撤回潜伏期以及后爪对冷刺激的撤回频率来评估热痛觉过敏。还在脊神经损伤的小鼠中研究了全身给予吗啡、κ-阿片激动剂U50488H和纳洛酮对机械和热刺激反应的影响。
脊神经损伤后，野生型小鼠对神经损伤同侧的机械、热和冷刺激的反应性增加。μ-阿片受体基因敲除小鼠不仅在神经损伤的爪中具有更明显的机械性异常性疼痛，而且对机械刺激表现出对侧异常性疼痛。μ-阿片受体基因敲除小鼠和野生型动物对热刺激的痛觉过敏相似。吗啡在野生型小鼠中剂量依赖性地降低机械性异常性疼痛（皮下注射3 - 30 mg/kg）——这种作用在杂合小鼠中减弱，在纯合μ-阿片受体基因敲除小鼠中不存在。κ-阿片激动剂U50488H（皮下注射3 - 10 mg/kg）减弱了野生型、杂合型和纯合型μ-阿片受体小鼠的机械性异常性疼痛。野生型小鼠中的纳洛酮导致对机械刺激的同侧和对侧异常性疼痛增强，类似于在μ-阿片受体基因敲除小鼠中观察到的疼痛行为。
作者的观察结果表明：（1）单侧神经损伤诱导内源性μ-阿片受体介导的抑制的双侧紧张性激活，该激活减弱机械性异常性疼痛但不减弱热痛觉过敏；（2）μ-和κ-阿片激动剂均减弱小鼠的神经性疼痛；（3）吗啡的抗痛觉过敏作用主要通过μ-阿片受体介导。
