HISTAMINERGIC MECHANISMS OF ANTINOCICEPTION

描述(申请人提供)：从组胺拮抗剂中提取的一种新的止痛药已经被发现。这种原型药物(命名为Improgan)在注射到大脑后表现出以下特征：A)在两种啮齿动物中高效地减弱热和机械伤害感，B)运动功能没有损害，C)独立于已知的阿片或组胺受体，D)缺乏对日常剂量的耐受性。以下在大鼠和小鼠身上的实验将揭示其作用机制，并评估该药物在临床相关疼痛模型中的疗效：(1)尚未发现该受体。用~3H-西咪替丁进行的放射性配基结合研究将检验这种配基与脑内非特异性受体结合的假设。这项试验的验证将导致发现不正确的受体，并开发作用于该受体的新药。(2)在炎症性和神经病理性伤害性模型上观察异丙肾上腺素对临床相关疼痛的疗效。(3)延髓头端腹内侧(RVM)的“离细胞”在RVM介导的镇痛中起关键作用，而不适当的药物可能激活这些细胞。将进行单单位记录、微量注射、行为测试和离子导入的组合，以揭示不当抗伤害感觉的神经生理学基础。(4)大麻素CBJ拮抗剂可阻断孕酮的抗伤害作用，但该药缺乏对CBI受体的亲和力。对大麻素类药物和反义寡核苷酸的体内研究将证实CBI受体和内源性大麻素(内源性大麻素)在临时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药物的作用机制，并导致新的非阿片类药物治疗疼痛的开发。

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.