Department of Pharmacology, School of Basic Medical Sciences; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Neurosci Bull. 2013 Jun;29(3):261-9. doi: 10.1007/s12264-013-1316-0. Epub 2013 Mar 13.
The present study was designed to investigate the effects of histamine on spontaneous neuropathic pain (NP) induced by peripheral axotomy. Rats and mice were subjected to complete transection of the left sciatic and saphenous nerves to induce spontaneous NP (the neuroma model). Rats were then treated with drugs once daily for 30 days (histidine and loratadine, i.p.) or 21 days (histamine, i.c.v.). Autotomy behavior was scored daily until day 50 post-operation (PO). On days 14 to 21 PO, some rats in the control group were subjected to single-fiber recording. Autotomy behavior was also monitored daily in histidine decarboxylase (the key enzyme for histamine synthesis) knockout (HDC(-/-)) and wild-type mice for 42 days. We found that both histidine (500 mg/kg) (a precursor of histamine that increases histamine levels in the tissues) and histamine (50 μg/5 μL) significantly suppressed autotomy behavior in rats. HDC(-/-) mice lacking endogenous histamine showed higher levels of autotomy than the wild-type. In addition, the analgesic effect of histidine was not antagonized by loratadine (a peripherally-acting H1 receptor antagonist), while loratadine alone significantly suppressed autotomy. Electrophysiological recording showed that ectopic spontaneous discharges from the neuroma were blocked by systemic diphenhydramine (an H1 receptor antagonist). Our results suggest that histamine plays an important role in spontaneous NP. It is likely that histamine in the central nervous system is analgesic, while in the periphery, via H1 receptors, it is algesic. This study justifies the avoidance of a histamine-rich diet and the use of peripherally-acting H1 receptor antagonists as well as agents that improve histamine action in the central nervous system in patients with spontaneous NP.
本研究旨在探讨组胺对周围神经切断引起的自发性神经病理性疼痛（NP）的影响。大鼠和小鼠接受左侧坐骨神经和隐神经完全横断，以诱导自发性 NP（神经瘤模型）。然后，大鼠每天接受药物治疗 30 天（组氨酸和氯雷他定，腹腔注射）或 21 天（组胺，脑室内注射）。自截行为每天评分，直到术后第 50 天（PO）。在 PO 的第 14 天到第 21 天，对照组中的一些大鼠进行了单纤维记录。在 42 天内，组胺脱羧酶（组胺合成的关键酶）敲除（HDC(-/-)）和野生型小鼠中也每天监测自截行为。我们发现，组氨酸（500mg/kg）（组胺的前体，可增加组织中的组胺水平）和组胺（50μg/5μL）均显著抑制大鼠的自截行为。缺乏内源性组胺的 HDC(-/-)小鼠的自截行为水平高于野生型。此外，组氨酸的镇痛作用不受氯雷他定（外周 H1 受体拮抗剂）拮抗，而氯雷他定本身可显著抑制自截。电生理记录显示，全身性苯海拉明（H1 受体拮抗剂）阻断神经瘤的异位自发性放电。我们的结果表明，组胺在自发性 NP 中起重要作用。可能是中枢神经系统中的组胺具有镇痛作用，而在外周通过 H1 受体，它具有致痛作用。这项研究证明了避免富含组胺的饮食和使用外周作用的 H1 受体拮抗剂以及改善中枢神经系统中组胺作用的药物的合理性，适用于自发性 NP 患者。
