Pertovaara A
Department of Physiology, University of Helsinki, Finland.
Prog Neurobiol. 1993 Jun;40(6):691-709. doi: 10.1016/0301-0082(93)90011-g.
Alpha-2-adrenoceptor agonists can activate varying antinociceptive mechanisms depending on the dose and the route of administration, although the main site for their antinociceptive effect in physiological pain conditions seems to be the spinal dorsal horn. In this paper the investigations on the underlying mechanisms are reviewed, with particular emphasis on novel studies using a highly selective and potent alpha-2-adrenoceptor agonist medetomidine. In behavioral studies alpha-2-adrenoceptor agonists, including medetomidine, produce antinociception following systemic administration or local application to the spinal cord. Following systemic administrations the antinociceptive effect at subanesthetic doses in physiological pain conditions is weak and the affective-motivational component of pain is more sensitive to suppression than sensory-discriminative aspect of pain. Electrophysiological studies at the spinal cord level indicate that alpha-2-adrenoceptor agonists suppress the responses of the pain-relay neurons both due to pre- and postsynaptic spinal cord level mechanisms following systemic or intrathecal drug administration. The antinociceptive effect at the spinal cord level is selective, since non-nociceptive signals are not attenuated. According to electrophysiological single neuron recordings, nociceptive signals at supraspinal levels are more sensitive to antinociceptive effects of systemically administered alpha-2-adrenoceptor agonists than nociceptive signals at the spinal cord level. However, according to immunocytochemical imaging of immediate early gene response to noxious stimulation, medetomidine strongly suppresses responses at the spinal cord level already following a systemic dose (100 micrograms/kg i.p.) which is not enough to produce a significant suppression of spinally-initiated nocifensive tail reflexes nor the electrophysiologically recorded responses to nociceptive spinal neurons. Thus, the higher sensitivity of supraspinal neuronal responses and their behavioral correlates to the antinoceptive effect of medetomidine obviously reflects the cumulative effect of medetomidine at several areas along the polysynaptic pathway to the rostral parts of the brain. Paradoxically, the response of immediate early genes in the medial thalamic neurons is only slightly, influenced by antinociceptive doses of medetomidine. Alpha-2-adrenoceptors have significant interactions with other receptors (e.g. opioid, serotonin and muscarine) in producing antinociception at the spinal cord level.
α2肾上腺素能激动剂可根据剂量和给药途径激活不同的抗伤害感受机制，尽管在生理疼痛状态下其抗伤害感受作用的主要部位似乎是脊髓背角。本文综述了对其潜在机制的研究，特别强调了使用高选择性和强效α2肾上腺素能激动剂美托咪定的新研究。在行为学研究中，包括美托咪定在内的α2肾上腺素能激动剂在全身给药或局部应用于脊髓后可产生抗伤害感受作用。全身给药后，在生理疼痛状态下亚麻醉剂量的抗伤害感受作用较弱，且疼痛的情感动机成分比疼痛的感觉辨别成分对抑制更敏感。脊髓水平的电生理研究表明，α2肾上腺素能激动剂在全身或鞘内给药后，由于脊髓水平的突触前和突触后机制，抑制了痛觉传递神经元的反应。脊髓水平的抗伤害感受作用具有选择性，因为非伤害性信号未被减弱。根据电生理单神经元记录，与脊髓水平的伤害性信号相比，脊髓上水平的伤害性信号对全身给药的α2肾上腺素能激动剂的抗伤害感受作用更敏感。然而，根据对有害刺激的即时早期基因反应的免疫细胞化学成像，美托咪定在全身剂量（100微克/千克腹腔注射）后就强烈抑制脊髓水平的反应，该剂量不足以显著抑制脊髓引发的伤害性尾部反射，也不足以抑制对伤害性脊髓神经元的电生理记录反应。因此，脊髓上神经元反应及其行为相关性对美托咪定抗伤害感受作用的更高敏感性显然反映了美托咪定在沿多突触通路至脑前部的几个区域的累积作用。矛盾之处在于，中脑丘神经元中即时早期基因的反应仅受到抗伤害感受剂量美托咪定的轻微影响。α2肾上腺素能受体在脊髓水平产生抗伤害感受作用时与其他受体（如阿片类、5-羟色胺和毒蕈碱）有显著相互作用。
