Biella Gabriele E M, Groppetti Antonio, Novelli Antonello, Fernández-Sánchez Maria Teresa, Manfredi Barbara, Sotgiu Maria Luisa
Institute of Bioimmagini e Fisiologia Molecolare, C.N.R., Segrate, Milan, Italy.
J Neurotrauma. 2003 Jun;20(6):593-601. doi: 10.1089/089771503767168519.
N-methyl-D-aspartic acid (NMDA) is an agonist at the homonymous receptor implicated in the development of neuronal sensitization and its behavioral correlates. An effective modulation of the NMDA effects, achieved also by uncompetitive antagonists, could contribute to controlling pain symptoms in several neuropathic syndromes. Because nefopam is a known analgesic derivative of orphenadrine and of its congener diphenhydramine, both uncompetitive NMDA receptor antagonists, we tested the effect of nefopam on the developing pain and neuronal anomalies in an animal model of chronic pain with NMDA receptor involvement. A single intraperitoneal injection of nefopam was administered twenty minutes prior to the chronic constriction injury of the sciatic nerve (CCI rats). In the first 10 days, nefopam (30 mg/kg) significantly decreased behavioral signs of neuropathic pain and the stimulus-evoked electrophysiological anomalies in recordings at 14 days, with only slight manifestation afterwards. The dose of 20 mg/kg was ineffective. Nefopam injected after constriction was ineffective. In normal non-operated rats, Nefopam had no effect on the electrophysiological and behavioral parameters. Iontophoretic nefopam (1 mM, 50-80 nA, positive current) in normal rats did not change the spontaneous neuronal activity, but reduced the mean response to noxious stimuli and the concurrent iontophoretic NMDA evoked activity. In CCI rats, iontophoretic nefopam did not significantly modify the spontaneous hyperactivity but reduced significantly both the frequency of the responses to noxious stimuli, and the duration of the afterdischarge. We propose that nefopam exerts a preventive analgesic effect, with a possible role in modulating NMDA receptor-mediated effects in central sensitization.
N-甲基-D-天冬氨酸（NMDA）是一种作用于同名受体的激动剂，该受体与神经元致敏及其行为关联的发展有关。非竞争性拮抗剂也能有效调节NMDA的作用，这可能有助于控制多种神经病理性综合征的疼痛症状。由于奈福泮是已知的奥芬那君及其同类物苯海拉明的镇痛衍生物，二者均为非竞争性NMDA受体拮抗剂，我们在一个涉及NMDA受体的慢性疼痛动物模型中测试了奈福泮对正在发展的疼痛和神经元异常的影响。在坐骨神经慢性缩窄损伤（CCI大鼠）前20分钟腹腔注射一次奈福泮。在最初10天，奈福泮（30mg/kg）显著减轻了神经病理性疼痛的行为体征以及14天时记录的刺激诱发电生理异常，之后仅有轻微表现。20mg/kg的剂量无效。缩窄后注射奈福泮无效。在正常未手术的大鼠中，奈福泮对电生理和行为参数无影响。正常大鼠中离子导入奈福泮（1mM，50 - 80nA，正向电流）不改变自发神经元活动，但降低了对有害刺激的平均反应以及同时离子导入NMDA诱发的活动。在CCI大鼠中，离子导入奈福泮未显著改变自发活动亢进，但显著降低了对有害刺激的反应频率以及后放电的持续时间。我们认为奈福泮发挥预防性镇痛作用，可能在调节中枢致敏中NMDA受体介导的效应方面发挥作用。
