HISTAMINERGIC MECHANISMS OF ANTINOCICEPTION

已经发现了一类新的止痛药，其来源于组胺拮抗剂。原型 （名为improgan）注射入脑后表现出以下特点：A）高效 在两种啮齿类动物中热和机械伤害感受的衰减，B）运动损伤的不存在 功能，C）不依赖于已知的阿片样物质或组胺受体，和D）缺乏对每日 剂量。以下在大鼠和小鼠中的实验将揭示Improgan的作用机制， 评价该药在临床相关疼痛模型中的疗效：（1）Improgan受体没有 还没被发现3 H-西咪替丁的放射性配体结合研究将检验该配体 与大脑的异丙受体结合该测定的验证将导致发现不适当的 受体，并开发作用于该受体的新药。(2)Improgan的影响 炎性和神经性伤害性模型将评估这种药物在临床相关疾病中的功效。 痛苦(3)延髓头端腹内侧（RVM）中的“关闭细胞”对于RVM介导的镇痛至关重要， improgan似乎激活了这些细胞。结合单个单元记录，显微注射， 将进行行为测试和离子导入以揭示改善的神经生理学基础。 抗伤害感受(4)大麻素CBj拮抗剂阻断了Imperan的镇痛作用，但这种药物缺乏 对CBi受体的亲和力。大麻素药物和反义寡核苷酸的体内研究将 验证CBi受体和内源性大麻素（endocannabinoids）在原发性高血压中的机制作用。 抗伤害感受这些药理学家、神经生理学家和 化学家将发现这类新型药物的作用机制，并导致开发 新的非阿片类药物治疗疼痛。

A new class of pain-relieving drugs, derived from histamine antagonists, has been discovered. The prototype (named improgan) shows the following characteristics after injection into the brain: A) highly effective attenuation of thermal and mechanical nociception in two rodent species, B) absence of impairment of motor function, C) independence from known opioid or histamine receptors, and D) lack of tolerance with daily dosing. The experiments below in rats and mice will reveal the mechanism of action of improgan, and evaluate the efficacy of this drug in clinically relevant pain models: (1) The improgan receptor has not yet been discovered. Radioligand binding studies with 3H-cimetidine will test the hypothesis that this ligand binds to the brain improgan receptor. Validation of this assay will lead to discovery of the improgan receptor, and to the development of new drugs acting on this receptor. (2) The effects of improgan on inflammatory and neuropathic nociceptive models will evaluate the efficacy of this drug in clinically relevant pain. (3) "Off-cells" in the rostral ventromedial medulla (RVM) are crucial for RVM-mediated analgesia, and improgan appears to activate these cells. Combinations of single unit recording, microinjections, behavioral testing and iontophoresis will beperformed to reveal the neurophysiological basisfor improgan antinociception. (4) Improgan antinociception is blocked by cannabinoid CBj antagonists, yet this drug lacks affinity for the CBi receptor. In vivo studies with cannabinoid drugs and anti-sense oligonucleotides will verify mechanistic rolesfor CBi receptors and endogenous cannabinoids (endocannabinoids) in improgan antinociception. These collaborative experiments between pharmacologists, neurophysiologists and chemists will discover the mechanism of action of this novel class of agents and lead to the development of new, non-opioid pharmacotherapies for pain.