Khasar S G, Green P G, Chou B, Levine J D
Department of Medicine, University of California, San Francisco 94143-0452, USA.
Neuroscience. 1995 May;66(2):427-32. doi: 10.1016/0306-4522(94)00562-j.
We have previously shown that norepinephrine can produce hyperalgesia via an alpha 2-adrenergic receptor mechanism. The alpha 2-adrenergic receptor agonist clonidine has, however, also been shown to produce peripheral analgesia. In view of the multiple alpha 2-subtypes currently known (i.e. alpha 2A, alpha 2B and alpha 2C), we evaluate the alpha 2-receptor subtypes mediating norepinephrine-induced peripheral hyperalgesia and clonidine analgesia. Norepinephrine and the alpha 2-adrenergic agonists clonidine and UK 14,304 (1-1000 ng), when co-injected with the calcium ionophore A23187 (1000 ng) produced dose-dependent hyperalgesia in the Randall-Selitto paw withdrawal test. Norepinephrine (100 ng) hyperalgesia was dose-dependently antagonized by alpha 2-adrenergic receptor antagonists. From the estimated ID50, the rank order of potency was: SK&F 104856 (alpha 2B) approximately imiloxan (alpha 2B) > rauwolscine (alpha 2C) >> BRL 44408 (alpha 2A). Norepinephrine hyperalgesia was not significantly affected by pertussis-toxin treatment. Prostaglandin E2 (100 ng) hyperalgesia was inhibited dose-dependently, by clonidine and UK 14,304. Rauwolscine was more potent in reversing the inhibitory effect of clonidine on prostaglandin E2 than imiloxan while BRL 44408 was ineffective. The inhibitory effect of clonidine on prostaglandin E2 hyperalgesia was reversed by pertussis toxin. These data suggest that alpha 2B-subtype receptors mediate (norepinephrine hyperalgesia while the antinociceptive effect of alpha 2-agonist is mediated by the alpha 2C-subtype receptor. Differential coupling of these receptor subtypes to second messenger systems and location on different cell types in the rat paw may explain, at least in part, their differential responses to alpha 2-agonist stimulation, leading to hyperalgesia and analgesia.
我们之前已经表明，去甲肾上腺素可通过α2-肾上腺素能受体机制产生痛觉过敏。然而，α2-肾上腺素能受体激动剂可乐定也已被证明可产生外周镇痛作用。鉴于目前已知多种α2-亚型（即α2A、α2B和α2C），我们评估介导去甲肾上腺素诱导的外周痛觉过敏和可乐定镇痛作用的α2-受体亚型。在Randall-Selitto paw withdrawal试验中，当去甲肾上腺素以及α2-肾上腺素能激动剂可乐定和UK 14,304（1 - 1000 ng）与钙离子载体A23187（1000 ng）共同注射时，会产生剂量依赖性的痛觉过敏。α2-肾上腺素能受体拮抗剂可剂量依赖性地拮抗去甲肾上腺素（100 ng）引起的痛觉过敏。根据估计的ID50，效力顺序为：SK&F 104856（α2B）约等于咪洛昔生（α2B）>育亨宾（α2C）>>BRL 44408（α2A）。百日咳毒素处理对去甲肾上腺素引起的痛觉过敏没有显著影响。前列腺素E2（100 ng）引起的痛觉过敏可被可乐定和UK 14,304剂量依赖性地抑制。育亨宾在逆转可乐定对前列腺素E2的抑制作用方面比咪洛昔生更有效，而BRL 44408则无效。可乐定对前列腺素E2痛觉过敏的抑制作用可被百日咳毒素逆转。这些数据表明，α2B-亚型受体介导（去甲肾上腺素痛觉过敏），而α2-激动剂的抗伤害感受作用由α2C-亚型受体介导。这些受体亚型与第二信使系统的差异偶联以及在大鼠爪中不同细胞类型上的定位，可能至少部分解释了它们对α2-激动剂刺激的不同反应，从而导致痛觉过敏和镇痛。
