HISTAMINERGIC MECHANISMS OF ANTINOCICEPTION

组胺能抗伤害机制

• 批准号: 7030617
• 负责人: LINDSAY HOUGH
• 金额: $ 39.64万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7030617
• 关键词: analgesics; antihistamines; drug interactions; drug metabolism; histamine; histamine receptor; hyperalgesia; laboratory rat; microdialysis; morphine; neuropharmacology; opioid receptor; periaqueductal gray matter; pons; stimulant /agonist

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.

描述（由申请人提供）：已经发现了一种新的疼痛降低药物，这些药物是从组胺拮抗剂中得出的。原型（命名为Impogan）在注入大脑后显示了以下特征：a）在两种啮齿动物物种中对热和机械伤害感受的高效衰减，b）b）缺乏运动功能损害，c）脱离已知的阿片类药物或组织胺受体独立，d）缺乏每日剂量的耐受性。以下大鼠和小鼠的实验将揭示Impogan作用机理，并评估该药物在临床相关的疼痛模型中的功效：（1）尚未发现Imbogan受体。使用3H-二甲胺的放射性结合研究将检验该配体与大脑Imbogan受体结合的假设。该测定法的验证将导致发现Imbogan受体，并开发出对该受体作用的新药。 （2）Impogan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）延髓腹侧髓质（RVM）中的“非细胞”对于RVM介导的镇痛至关重要，而Improgan似乎会激活这些细胞。将进行单个单位记录，显微注射，行为测试和离子噬菌体的组合，以揭示神经生理学基础，以造成抗伤害感受。 （4）Imbogan抗伤害感受被大麻素CBJ拮抗剂阻塞，但该药物对CBI受体缺乏亲和力。大麻素药物和抗义寡核苷酸的体内研究将验证CBI受体和内源性大麻素（内源性大麻素）在Improgan抗伤害感受中的机理作用。药理学家，神经生理学家和化学家之间的这些协作实验将发现这种新型代理的作用机理，并导致新的非阿片类药物疗法的疼痛发展。