Pertovaara A, Kauppila T, Jyväsjärvi E, Kalso E
Department of Physiology, University of Helsinki, Finland.
Neuroscience. 1991;44(3):705-14. doi: 10.1016/0306-4522(91)90089-7.
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.
通过对大鼠三种不同类型感觉神经元群外周诱发反应进行电生理记录，研究了全身给药的美托咪定（一种选择性α-2肾上腺素能受体激动剂）的作用：内侧丘脑神经元仅在伤害性强度下对机械性皮肤刺激有反应，脊髓的脊髓丘脑束神经元仅在伤害性强度下或对伤害性强度的机械性皮肤刺激有差异反应，以及具有上行投射的低阈值机械感受性脊髓背角神经元。将神经元效应与在完整和脊髓大鼠的机械性和热诱导伤害性尾巴反射试验中获得的行为数据进行比较。通过全身（1.5mg/kg，腹腔注射）或鞘内（25μg）给予阿替美唑（一种选择性α-2肾上腺素能受体拮抗剂）来尝试逆转抗伤害感受作用。全身给药的美托咪定对伤害性内侧丘脑和脊髓丘脑束神经元的诱发反应产生了阿替美唑可逆的、剂量依赖性的抑制作用。抑制伤害性内侧丘脑神经元（100μg/kg）的诱发反应（半数最大抑制）所需的美托咪定剂量低于伤害性脊髓丘脑束神经元（300μg/kg）。伤害性脊髓丘脑束神经元诱发反应的降低伴随着自发活动的减少。脊髓低阈值机械感受性投射神经元的反应不受美托咪定（30 - 300μg/kg）影响。用300μg/kg（麻醉）剂量的美托咪定进行的反射研究表明，在完整且未使用其他药物的大鼠中，美托咪定使对尾巴夹捏和热刺激的伤害性反射反应潜伏期显著延长；全身给药的美托咪定的这些抗伤害感受作用可被全身和鞘内应用的阿替美唑逆转。在脊髓大鼠中，全身应用美托咪定（300μg/kg）也使甩尾潜伏期显著延长，这可被全身应用的阿替美唑逆转。结果表明，全身应用高麻醉剂量的美托咪定（300μg/kg）可通过作用于α-2肾上腺素能受体，抑制由于脊髓节段机制引起的伤害性感觉神经元和反射反应。这种脊髓效应是对伤害性神经元反应具有选择性的，并且如自发活动同时减少所表明的，至少部分是突触后效应。在较低的、亚麻醉（但有镇静作用）剂量（百μg/kg）下，全身应用美托咪定的抗伤害感受作用可由脊髓上的α-2肾上腺素能机制来解释。
