Nornicotine for Treatment of Pain

描述（由申请人提供）：在美国，疼痛的治疗是一个重要的健康问题，每年影响数千万人。慢性疼痛（癌症和非恶性疼痛）管理是一项特别具有挑战性的任务。用于治疗疼痛的主要药物组是阿片类药物(例如。吗啡)和非甾体类抗炎药（如NSAID）。布洛芬,塞来昔布)。与副作用和疗效相关的显着局限性，最明显的是慢性神经性疼痛综合征(例如。糖尿病性神经病变、aids相关神经病变、复杂局部疼痛综合征、脊髓损伤)均与这两类药物同时存在。具有改善疗效/副作用的新型疼痛治疗药物将带来显著的社会效益。作用于烟碱乙酰胆碱受体的药物是一类潜在重要的新型镇痛药物。其中一种药物，去甲尼古丁，一种尼古丁的活性代谢物，是一种很有希望的镇痛药物。与尼古丁相比，这种药物具有更好的药代动力学特征（半衰期更长，在中枢神经系统中积累，生物利用度更高）和更小的毒性。去甲尼古丁有S(-)-和R（+）对映体两种形式，这两种对映体在镇痛效力和副作用上有所不同。因此，有理由期望一种对映体具有更大的镇痛效果和可接受的副作用。我们的初步研究结果支持了这种可能性，并且在其他镇痛药物(如。n -甲基- d -天冬氨酸受体拮抗剂)。这项I期STTR研究的主要目的是检测S(-)-和/或R(+)-去甲尼古丁在啮齿动物急性（热爪戒断）、强张性炎症（足底注射福尔马林）和神经性疼痛（坐骨神经收缩）模型中的抗痛觉、抗痛觉过敏和抗异动活性。还将检查运动活动和运动协调（rotorod），以确定去尼古丁对映体的抗感觉活性是否在没有明显运动损伤的情况下发生。最后，我们将确定当S(-)-和/或R(+)-去甲尼古丁与阿片类药物（吗啡）联合使用时是否产生协同（超加性）抗痛觉作用。多药治疗疼痛的方法在临床上已经很好地建立起来，这种联合使用每种药物的剂量较低，并且有望减少每种药物相关的副作用。具体目的是：1)研究S(-)-和R(+)-去甲尼古丁在伤害性、神经性和强直性炎性疼痛大鼠模型中的抗痛觉性、抗痛觉过敏和抗异动作用；2)表征S(-)-和R(+)-去甲尼古丁对运动活动和运动协调的影响；3)研究吗啡与S（-)-和R(+)-去甲尼古丁联用在伤害性疼痛大鼠模型中的协同抗痛觉性作用；4）合成S(-)-和R(+)-去甲尼古丁用于临床前抗痛觉性和副作用研究。这项I期STTR研究的结果对于开发一种适合治疗疼痛的临床有用的镇痛药物（去尼古丁对映体）的长期目标（II期研究）非常重要。在美国，疼痛的治疗是一个严重的健康问题，每年影响着数千万人。新的疼痛治疗药物，特别是慢性疼痛（癌症相关的和非恶性的）将带来显著的社会效益。这个研究项目的重点是开发一种新的止痛剂，去甲尼古丁，用于疼痛管理。

DESCRIPTION (provided by applicant): The treatment of pain is a critical health issue affecting tens of millions of people annually in the US. Chronic pain (cancer and nonmalignant pain) management is an especially challenging task. The primary groups of agents that have been used to treat pain are the opioids (eg. morphine) and the nonsteroidal antiinflammatory drugs (NSAID's; eg. ibuprofen, celecoxib). Significant limitations related to side effects and efficacy, most notably for chronic neuropathic pain syndromes (eg. diabetic neuropathy, AID's related neuropathy, complex regional pain syndrome, spinal cord injury) exist with these two classes of drugs. New therapeutic agents for pain with an improved efficacy/side effect profile would result in significant societal benefit. Drugs acting at nicotinic acetylcholine receptors are a potentially important new class of analgesic drugs. One such drug, nornicotine, an active metabolite of nicotine, is a promising analgesic candidate. This drug has both a better pharmacokinetic profile (longer half-life, accumulation in the CNS, greater bioavailability) and less toxicity compared to nicotine. Nornicotine has both S(-)- and R(+) enantiomeric forms and the enantiomers appear to differ in analgesic potency and side effects. Thus, it is reasonable to expect that one enantiomer will possess greater analgesic efficacy with acceptable side effects. Our preliminary findings support this possibility and precedent exists for this concept with other analgesic drugs (eg. N-methyl-D- aspartate receptor antagonists). The major goal of this Phase I STTR study is to examine antinociceptive, anti- hyperalgesic and anti-allodynic activity of S(-)- and/or R(+)-nornicotine in rodent models of acute (thermal paw withdrawal), tonic inflammatory (intraplantar formalin injection) and neuropathic pain (sciatic nerve constriction). Locomotor activity and motor coordination (rotorod) will also be examined to determine if the antinociceptive activity of the nornicotine enantiomers occurs without significant motor impairment. Finally, we will determine if there is a synergistic (supra-additive) antinociceptive effect produced when S(-)- and/or R(+)- nornicotine is used in combination with an opioid (morphine). Multi-drug approaches to pain management are clinically well established and such a combination utilizes lower doses of each drug and would be expected to diminish side effects associated with each agent. The Specific Aims are to: 1) Characterize the antinociceptive, anti-hyperalgesic and anti-allodynic effects of S(-)- and R(+)-nornicotine in a rat model of nociceptive, neuropathic and tonic inflammatory pain; 2) Characterize the effects of S(-)- and R(+)-nornicotine on locomotor activity and motor coordination; 3) Characterize the synergistic antinociceptive effect of morphine in combination with S(-)- and R(+)-nornicotine in a rat model of nociceptive pain and 4) Perform synthesis of S(-)- and R(+)-nornicotine for use in the preclinical antinociception and side effect studies. Findings from this Phase I STTR study are important to the long term goal (Phase II studies) of developing a clinically useful analgesic drug (nornicotine enantiomer) suitable for management of pain. The treatment of pain is a critical health issue affecting tens of millions of people annually in the US. New therapeutic agents for pain, especially for chronic pain (cancer-related and nonmalignant) would result in significant societal benefit. This research project focuses on the development of a novel analgesic agent, nornicotine, for pain management.