Kingery Wade S, Guo Tian Z, Davies Frances M, Limbird Lee, Maze Mervyn
Department of Functional Restoration, Stanford University, Stanford, CA, USA Department of Physical Medicine and Rehabilitation, Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304, USA Department of Anesthesia, Stanford University, Stanford, CA, USA Department of Anesthesiology Services, Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304, USA Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
Pain. 2000 Apr;85(3):345-358. doi: 10.1016/S0304-3959(99)00286-9.
We have addressed the role of the sympathetic nervous system in the development and maintenance of neuropathic pain. Using a new neuropathic mouse model, we examined the development of hyperalgesia in transgenic mice lacking functional alpha(2A) adrenoceptors and in sympathectomized wild-type mice, to determine if sympathetic-sensory coupling generates hyperalgesia. The development of neuropathic heat hyperalgesia required the presence of both the alpha(2A) adrenoceptor and the sympathetic postganglionic neuron (SPGN), but the development of mechanical hyperalgesia did not require either the alpha(2A) adrenoceptor or the SPGN, indicating different mechanisms of sensitization. These results suggest that the development of neuropathic heat hyperalgesia, but not mechanical hyperalgesia, requires sympathetic-sensory coupling in the peripheral nervous system. Nerve injury enhanced the analgesic efficacy of the alpha(2) adrenoceptor agonist dexmedetomidine, and paradoxically also induced an analgesic response to alpha(2) adrenoceptor antagonists. The alpha(2) agonist-evoked analgesia to mechanical stimuli was mediated by activating central alpha(2A) adrenoceptors, possibly at the spinal level. The peripherally restricted alpha(2) antagonist L659,066 evoked analgesia for heat, but not for mechanical stimuli, findings which support the hypothesis that the peripheral alpha(2) adrenoceptor plays a role in both the development and the maintenance of neuropathic heat hyperalgesia. The alpha(2) antagonist-evoked analgesia for heat stimuli was mediated by blocking peripheral and probably central alpha(2) adrenoceptors, while the analgesia for mechanical stimuli was mediated by blocking central alpha(2A) adrenoceptors. Intradermal injections with an alpha(2) agonist or antagonist had no effect on nociceptive thresholds, indicating that sympathetic-sensory coupling at the level of the cutaneous nociceptor did not contribute to the maintenance of neuropathic hyperalgesia.
我们已经探讨了交感神经系统在神经性疼痛的发生和维持中的作用。利用一种新的神经性小鼠模型，我们研究了缺乏功能性α(2A)肾上腺素能受体的转基因小鼠和交感神经切除的野生型小鼠中痛觉过敏的发展情况，以确定交感-感觉耦合是否会产生痛觉过敏。神经性热痛觉过敏的发展需要α(2A)肾上腺素能受体和交感神经节后神经元(SPGN)同时存在，但机械性痛觉过敏的发展既不需要α(2A)肾上腺素能受体也不需要SPGN，这表明存在不同的敏化机制。这些结果表明，神经性热痛觉过敏而非机械性痛觉过敏的发展需要外周神经系统中的交感-感觉耦合。神经损伤增强了α(2)肾上腺素能受体激动剂右美托咪定的镇痛效果，而且矛盾的是，还诱导了对α(2)肾上腺素能受体拮抗剂的镇痛反应。α(2)激动剂诱发的对机械刺激的镇痛作用是通过激活中枢α(2A)肾上腺素能受体介导的，可能是在脊髓水平。外周限制性α(2)拮抗剂L659,066诱发了对热刺激的镇痛作用，但对机械刺激无效，这些发现支持了外周α(2)肾上腺素能受体在神经性热痛觉过敏的发生和维持中均起作用这一假说。α(2)拮抗剂诱发的对热刺激的镇痛作用是通过阻断外周以及可能的中枢α(2)肾上腺素能受体介导的，而对机械刺激的镇痛作用是通过阻断中枢α(2A)肾上腺素能受体介导的。皮内注射α(2)激动剂或拮抗剂对伤害性感受阈值没有影响，这表明皮肤伤害感受器水平的交感-感觉耦合对神经性痛觉过敏的维持没有作用。
