The mechanism of 5-HT receptor agonists for inhibitory effect in neuropathic pain

一些证据表明，球脊髓5-羟色胺能（5-HT）系统介导对脊髓背角伤害性输入的抑制。在动物急性疼痛模型中，鞘内给予5-羟色胺具有抗伤害性作用。放射自显影研究显示脊髓中存在几种5-羟色胺受体。尽管存在一些争议，但已报道5-HT_<1A>, 5-HT_<1B>, 5-HT_2, 5-HT_3受体亚型参与脊髓5-HT的抗伤害感受作用。然而，这些脊髓5-HT受体亚型的激活是否抑制神经性疼痛尚不清楚。据报道，L5和L6脊髓神经的紧密结扎导致异常性疼痛。我们使用不同的激动剂和拮抗剂来比较不同脊髓5-羟色胺受体亚型在异痛症大鼠模型中的抗异痛症作用，发现只有鞘内给药的5-羟色胺受体激动剂产生抗异痛症作用（Pain 2001; 90: 173-179）。此外，我们研究了鞘内施用5-HT_2受体激动剂的抗异动作用机制。据报道，5-HT调节中枢神经系统的几种神经递质，如乙酰胆碱、去甲肾上腺素、GABA、腺苷等。因此，我们研究了其他相关的脊髓受体系统与5-HT_2受体激动剂抗异动作用的可能参与。从这些实验中，我们发现毒蕈碱受体拮抗剂逆转了鞘内施用的5-HT_2受体激动剂的抗异动作用（Brain Res, In Press）。脊髓中乙酰胆碱的释放和毒蕈碱受体的激活似乎至少部分参与了鞘内施用5-HT_2受体激动剂的抗异速运动作用。

Several lines of evidence demonstrated that bulbospinal serotonergic (5-HT) systems mediate suppression of nociceptive input to spinal dorsal horn. Intrathecally administered 5-HT has antinociceptive effects in acute pain models in animals. Autoradiographic studies have revealed that the presence of several 5-HT receptors in the spinal cord. Although some controversy persists, 5-HT_<1A>, 5-HT_<1B>, 5-HT_2, 5-HT_3 receptor subtypes have been reported to contribute to the antinociceptive action of 5-HT in the spinal cord. However, whether activation of these spinal 5-HT receptor subtypes inhibits neuropathic pain is unknown. It has been reported that tight ligation of spinal nerves L5 and L6 lead to allodynia. We used various agonists and antagonists to compare antiallodynic actions at each spinal 5-HT receptor subtypes in this rat model of allodynia, and found that only intrathecally administered 5-HT_2 receptor agonists produced antiallodynic action (Pain 2001 ; 90 : 173-179). Further, we examined the mechanisms of antiallodynic effect of intrathecally administered 5-HT_2 receptor agonists. It has been reported that 5-HT regulates several neurotransmitters, such as acetylcholine, noradrenaline, GABA, or adenosine, in central nervous system. Therefore, we investigated the possible involvement of other associated spinal receptor systems with respect to the antiallodynic action of a 5-HT_2 receptors agonist. From these experiments, we found that muscarinic receptor antagonists reversed the antiallodynic effects of intrathecally administered 5-HT_2 receptor agonists (Brain Res, In Press). Acetylcholine release and muscarinic receptor activation in the spinal cord appears to be, at least in part, involved in the antiallodynic action of an intrathecally administered 5-HT_2 receptor agonists.