Khandwala Hemal, Loomis Christopher W
School of Pharmacy, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, A1B 3V6 Canada Division of Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, A1B 3V6 Canada.
Pain. 1998 Jul;77(1):87-95. doi: 10.1016/S0304-3959(98)00086-4.
The blockade of spinal glycine receptors with intrathecal (i.t.) strychnine (STR) produces reversible, segmentally localized allodynia in the rat. The purpose of this study was: (1) to investigate the effect of the anticonvulsant agent, milacemide, a glycine pro-drug on STR-allodynia; (2) to compare this effect with that of milacemide on normal nociception (without STR); and (3) to determine the sensitivity of the anti-allodynic effect of milacemide to pretreatment with selective monoamine oxidase (MAO)-A (clorgyline) and MAO-B (L-deprenyl) inhibitors. Male Sprague-Dawley rats, fitted with chronic i.t. catheters, were lightly anesthetized with urethane. Hair deflection (HD) evoked maximum changes in blood pressure and heart rate were recorded from left carotid artery, and cortical electroencephalographic (EEG) activity was continuously monitored using subdermal needle electrodes before and after i.t. STR (40 microg). Rats were pretreated with a single intravenous (i.v.) injection of milacemide (100-600 mg/kg), 1 h before i.t. STR. To sustain the allodynic state, STR was injected every hour for up to 4 h. HD was applied to the affected dermatomes (2 min duration) using a cotton-tipped applicator at 5-min intervals for the duration of the STR effect. Normally innocuous HD elicited a marked increase in mean arterial blood pressure and heart rate, an immediate motor responses, and desynchronisation of EEG when applied to the cutaneous dermatomes affected by i.t. STR. Milacemide (100-600 mg/kg, i.v.) dose-dependently inhibited the heart rate and pressor responses (ED50 = 398 mg/kg; 95%CI = 196-873) and the motor responses (ED50 = 404 mg/kg; 95%CI = 275-727). Maximum inhibition was observed approximately 2 h after i.v. injection. The duration of action ranged from 3 h (400 mg/kg) to 4 h (600 mg/kg). Milacemide had no effect on the percent synchrony in the EEG. At the time of maximum inhibition of STR-allodynia (2 h post-infusion), responses evoked by noxious pinch were unaffected by milacemide. Pretreatment with L-deprenyl (3 mg/kg, i.p.), but not clorgyline (10 mg/kg, i.p.) significantly blocked the anti-allodynic effect of milacemide (600 mg/kg i.v). These data indicate that i.v. milacemide significantly attenuates the allodynia arising from spinal glycine receptor blockade, and are consistent with: (1) the selective modulation of low threshold afferent input by STR-sensitive, glycine interneurons in the rat spinal cord; and (2) the pharmacological actions of milacemide as a glycine pro-drug.
鞘内注射士的宁（STR）阻断大鼠脊髓甘氨酸受体可产生可逆的、节段性局限性痛觉过敏。本研究的目的是：（1）研究抗惊厥药米拉醋胺（一种甘氨酸前体药物）对STR诱导的痛觉过敏的影响；（2）将该作用与米拉醋胺对正常痛觉（无STR）的作用进行比较；（3）确定米拉醋胺抗痛觉过敏作用对选择性单胺氧化酶（MAO）-A（氯吉兰）和MAO-B（L-司立吉林）抑制剂预处理的敏感性。将装有慢性鞘内导管的雄性Sprague-Dawley大鼠用乌拉坦轻度麻醉。通过刺激毛发偏转（HD）诱发的血压和心率最大变化，从左颈动脉记录，并且在鞘内注射STR（40微克）前后，使用皮下针电极连续监测皮质脑电图（EEG）活动。在鞘内注射STR前1小时，大鼠经静脉单次注射米拉醋胺（100 - 600毫克/千克）进行预处理。为维持痛觉过敏状态，每小时注射STR，持续4小时。在STR作用期间，每隔5分钟用棉签对受影响的皮节施加HD（持续2分钟）。当对鞘内注射STR所影响的皮肤皮节施加通常无害的HD时，可引起平均动脉血压和心率显著升高、立即出现运动反应以及EEG去同步化。米拉醋胺（100 - 600毫克/千克，静脉注射）剂量依赖性地抑制心率和升压反应（ED50 = 398毫克/千克；95%置信区间 = 196 - 873）以及运动反应（ED50 = 404毫克/千克；95%置信区间 = 275 - 727）。静脉注射后约2小时观察到最大抑制作用。作用持续时间为3小时（400毫克/千克）至4小时（600毫克/千克）。米拉醋胺对EEG同步化百分比无影响。在STR诱导的痛觉过敏最大抑制时（输注后2小时），有害捏压诱发的反应不受米拉醋胺影响。用L-司立吉林（3毫克/千克，腹腔注射）预处理，但不用氯吉兰（10毫克/千克，腹腔注射）预处理，可显著阻断米拉醋胺（600毫克/千克，静脉注射）的抗痛觉过敏作用。这些数据表明，静脉注射米拉醋胺可显著减轻脊髓甘氨酸受体阻断引起的痛觉过敏，这与以下情况一致：（1）大鼠脊髓中STR敏感的甘氨酸中间神经元对低阈值传入输入的选择性调节；（2）米拉醋胺作为甘氨酸前体药物的药理作用。
