HISTAMINERGIC MECHANISMS OF ANTINOCICEPTION

描述（由申请人提供）：已发现一类新的止痛药，来源于组胺拮抗剂。原型（命名为improgan）在注射到脑中后显示出以下特征：A）在两种啮齿动物物种中高度有效地减弱热和机械伤害感受，B）不存在运动功能损害，C）不依赖于已知的阿片样物质或组胺受体，和D）缺乏每日给药的耐受性。以下大鼠和小鼠实验将揭示improgan的作用机制，并评价该药在临床相关疼痛模型中的疗效：（1）improgan受体尚未发现。3 H-西咪替丁的放射性配体结合研究将检验该配体与脑Improgan受体结合的假设。该试验的验证将导致improgan受体的发现，并开发出作用于该受体的新药。(2)Improgan对炎症和神经性伤害性模型的影响将评估该药物在临床相关疼痛中的疗效。(3)延髓头端腹内侧区（RVM）的“关闭细胞”对RVM介导的镇痛至关重要，Improgan似乎激活了这些细胞。将进行单个单位记录、显微注射、行为测试和离子电渗疗法的组合，以揭示不适当的抗伤害感受的神经生理学基础。(4)大麻素CB 1拮抗剂阻断了immecan抗伤害感受，但这种药物缺乏对CB 1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improgan抗伤害感受中的机制作用。药理学家，神经生理学家和化学家之间的这些合作实验将发现这类新型药物的作用机制，并导致新的非阿片类药物治疗疼痛的发展。

DESCRIPTION (provided by applicant): 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 be performed to reveal the neurophysiological basis for 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 roles for 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.