The effect of systemically administered medetomidine, a selective alpha-2-adrenoceptor agonist, was studied by electrophysiological recordings of the peripherally evoked responses of three different types of sensory neuronal populations in the rat: medial thalamic neurons exclusively responding to mechanical cutaneous stimuli at noxious intensities, spinothalamic tract neurons of the spinal cord responding exclusively or differentially to mechanical cutaneous stimuli at noxious intensities, and low-threshold mechanoreceptive spinal dorsal horn neurons with ascending projections. The neuronal effects were compared with the behavioral data obtained in mechanically and thermally induced nociceptive tail reflex tests in intact and spinal rats. A reversal of the antinociceptive effects was attempted by systemically (1.5 mg/kg, i.p.) or intrathecally (25 micrograms) administered atipamezole, a selective alpha-2-adrenoceptor antagonist. Systemically administered medetomidine produced an atipamezole-reversible, dose-dependent suppressive effect on the evoked responses of nociceptive medial thalamic and spinothalamic tract neurons. A lower dose of medetomidine was needed to suppress significantly (half-maximally) evoked responses of the nociceptive medial thalamic neurons (100 micrograms/kg) than those of the nociceptive spinothalamic tract neurons (300 micrograms/kg). The decrease of evoked responses of the nociceptive spinothalamic tract neurons was accompanied by a decrease in spontaneous activity. The responses of the low-threshold mechanoreceptive projection neurons of the spinal cord were not influenced by medetomidine (30-300 micrograms/kg). The reflex studies with a (anesthetic) medetomidine dose of 300 micrograms/kg indicated that in intact and otherwise drug-free rats, medetomidine produced a significant prolongation of the nociceptive reflex response latency to a tail-pinch and heat; these antinociceptive effects of systemic medetomidine were reversed by systemically and intrathecally applied atipamezole. In spinal rats systemically applied medetomidine (300 micrograms/kg) also produced a significant prolongation of the tail-flick latency, which was reversed by systemically applied atipamezole. The results suggest that a high anesthetic dose of systemically applied medetomidine (300 micrograms/kg) can suppress nociceptive sensory neuronal and reflex responses due to spinal segmental mechanisms through an action on alpha-2-adrenoceptors. This spinal effect is selective to responses of nociceptive neurons, and at least partly postsynaptic as indicated by the concomitant decrease in spontaneous activity. At a lower, subanesthetic (but sedative) dose (100 micrograms/kg) the antinociceptive effect of systemically applied medetomidine can be explained by supraspinal alpha-2-adrenergic mechanisms.

译文

通过电生理记录大鼠三种不同类型的感觉神经元群体的外周诱发反应,研究了全身给药的选择性alpha-2-adrenoceptor激动剂美托咪啶的作用: 内侧丘脑神经元仅对有害强度下的机械皮肤刺激作出反应,脊髓的脊髓丘脑束神经元对有害强度下的机械皮肤刺激仅响应或差异响应,以及具有上升投影的低阈值机械感受性脊髓背角神经元。将神经元效应与完整和脊髓大鼠的机械和热诱导的伤害性尾巴反射测试中获得的行为数据进行了比较。通过全身 (1.5 mg/kg,i.p.) 或鞘内 (25微克) 施用选择性alpha-2-adrenoceptor拮抗剂atipamezole,尝试逆转抗伤害感受作用。系统给药美托咪啶对伤害性丘脑内侧和脊髓丘脑道神经元的诱发反应产生了阿替帕美唑可逆的剂量依赖性抑制作用。与伤害性脊髓丘脑道神经元 (300微克/千克) 相比,需要较低剂量的美托咪啶来显着 (最大一半) 抑制伤害性丘脑内侧神经元的诱发反应 (100微克/千克)。伤害性脊髓丘脑束神经元诱发反应的减少伴随着自发活动的减少。脊髓低阈值机械感受投射神经元的反应不受美托咪啶 (30-300微克/千克) 的影响。(麻醉) 美托咪啶剂量为300微克/千克的反射研究表明,在完整的和其他无药物的大鼠中,美托咪啶产生了明显延长的伤害感受反射反应潜伏期,以尾捏和热; 全身和鞘内施用阿替帕美唑可逆转全身性美托咪啶的这些抗伤害感受作用。在脊髓大鼠中,全身应用美托咪啶 (300微克/千克) 也产生了明显的甩尾潜伏期延长,这被全身应用阿替帕美唑逆转。结果表明,高麻醉剂量的全身性美托咪啶 (300微克/千克) 可以通过对alpha-2-adrenoceptors的作用抑制脊髓节段机制引起的伤害性感觉神经元和反射反应。这种脊柱效应对伤害性神经元的反应是选择性的,并且至少部分是突触后的,如自发活动的伴随减少所表明的那样。在较低的亚麻醉 (但镇静) 剂量 (100微克/千克) 下,全身应用美托咪啶的抗伤害作用可以通过脊髓上 α-2-肾上腺素能机制来解释。

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