Jevtovic-Todorovic V, Wozniak D F, Powell S, Nardi A, Olney J W
Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Brain Res. 1998 Jan 19;781(1-2):202-11. doi: 10.1016/s0006-8993(97)01247-x.
Antagonists of NMDA glutamate receptors have been shown to alleviate neuropathic pain in rats and humans. However, NMDA antagonists can cause significant side effects ranging from behavioral disturbances to injury of neurons in the posterior cingulate/retrosplenial (PC/RS) cortex. We have found that alpha-2 adrenergic agonists prevent the PC/RS neurotoxic side effects of NMDA antagonists. In the present study of adult female rats subjected to sciatic nerve ligation (Bennett neuropathic pain model) and tested for paw withdrawal latency (PWL) following a thermal stimulus, we evaluated the ability of the NMDA antagonist, MK-801, to alleviate neuropathic pain either by itself or when administered together with the alpha-2 adrenergic agonist, clonidine. We found that MK-801, at a dose (0.05 mg/kg s.c.) that is known to cause mild hyperactivity but is subthreshold for producing PC/RS neurotoxic changes, relieved the neuropathic pain state associated with sciatic nerve ligation. However, the relief at this dose was very transient, and no neuropathic pain-relieving effect was observed at a lower dose (0. 025 mg/kg s.c.) of MK-801. Clonidine, at a dose (0.05 mg/kg s.c.) that prevents the cerebrocortical neurotoxic effects of MK-801, decreased sensitivity to the thermal stimulus equally under all conditions (ligated, sham ligated, unoperated), but did not specifically relieve neuropathic pain in the ligated limb. Combining this dose of clonidine with an ineffective dose (0.025 mg/kg s.c.) of MK-801 provided specific, complete and long lasting (up to 4 h) relief from neuropathic pain. Rats receiving this drug combination did not display hyperactivity or any other behavioral disturbance typically associated with MK-801 treatment, nor show neurotoxic changes in cerebrocortical neurons. In separate experiments on normal unoperated rats, we found that clonidine (0.05 mg/kg s.c.) counteracted the hyperactivity induced by MK-801 (0.05 mg/kg s.c.) and returned activity levels to a normal range. These findings signify that clonidine, which does not specifically relieve neuropathic pain, can potentiate the neuropathic pain-relieving action of MK-801, while also protecting against neurotoxicity and hyperactivity side effects of MK-801. The potentiation is of a sufficient magnitude that it permits cutting the MK-801 dose requirement in half, thereby achieving prolonged neuropathic pain relief while doubling the margin of safety against any type of side effect that might be mediated by blockade of NMDA receptors.
N-甲基-D-天冬氨酸（NMDA）谷氨酸受体拮抗剂已被证明可减轻大鼠和人类的神经性疼痛。然而，NMDA拮抗剂可引起显著的副作用，范围从行为障碍到后扣带回/压后皮质（PC/RS）神经元损伤。我们发现，α-2肾上腺素能激动剂可预防NMDA拮抗剂的PC/RS神经毒性副作用。在本研究中，成年雌性大鼠接受坐骨神经结扎（贝内特神经性疼痛模型），并在热刺激后测试爪退缩潜伏期（PWL），我们评估了NMDA拮抗剂MK-801单独或与α-2肾上腺素能激动剂可乐定联合给药时减轻神经性疼痛的能力。我们发现，MK-801以已知会引起轻度多动但低于产生PC/RS神经毒性变化阈值的剂量（0.05mg/kg皮下注射），缓解了与坐骨神经结扎相关的神经性疼痛状态。然而，该剂量下的缓解非常短暂，在较低剂量（0.025mg/kg皮下注射）的MK-801下未观察到神经性疼痛缓解作用。可乐定以预防MK-801脑皮质神经毒性作用的剂量（0.05mg/kg皮下注射），在所有条件下（结扎、假结扎、未手术）均同等程度地降低了对热刺激的敏感性，但未特异性缓解结扎肢体的神经性疼痛。将该剂量的可乐定与无效剂量（0.025mg/kg皮下注射）的MK-801联合使用，可特异性、完全且持久（长达4小时）地缓解神经性疼痛。接受这种药物组合的大鼠未表现出多动或任何其他通常与MK-801治疗相关的行为障碍，也未显示脑皮质神经元的神经毒性变化。在对正常未手术大鼠的单独实验中，我们发现可乐定（0.05mg/kg皮下注射）可抵消MK-801（0.05mg/kg皮下注射）诱导的多动，并使活动水平恢复到正常范围。这些发现表明，本身不能特异性缓解神经性疼痛的可乐定，可增强MK-801的神经性疼痛缓解作用，同时还可预防MK-801的神经毒性和多动副作用。这种增强作用的幅度足以将MK-801的剂量需求减半，从而在将针对任何可能由NMDA受体阻断介导的副作用的安全边际加倍的同时，实现延长的神经性疼痛缓解。
