Pharmacotherapy for Opiate Addiction and Toxicity

描述(申请人提供)：吗啡和其他鸦片类药物被广泛用于治疗剧烈疼痛，但它们产生的成瘾和副作用往往限制了它们的使用。本研究的目的是开发一种基于内源性多肽甘氨酰谷氨酰胺(Gly-Gin)的治疗吗啡成瘾和毒性的新方法。甘氨酸是由阿片肽--β-内啡肽在大脑中合成的。在临床前研究中，实验动物服用甘氨酸甘油可以预防吗啡引起的呼吸抑制和低血压，但不会影响吗啡缓解急性疼痛的能力。这项拟议的研究将检验甘氨酸抑制吗啡成瘾、耐受和依赖的假设，并确定甘氨酸是否影响慢性疼痛实验模型的吗啡止痛。目的1扩展Gly-gin预处理阻止对吗啡的条件性位置偏爱的获得的初步证据，并确定Gly-gin是否也抑制尼古丁的奖励效应。目的2将继续进行初步研究，表明Gly-gin预处理可抑制吗啡镇痛耐受性的形成，并减轻身体依赖的严重程度。目的3在慢性神经病理性疼痛和炎症性疼痛的实验模型中，测试甘氨酸是否影响吗啡的镇痛作用。我们希望发现甘氨酸不会干扰吗啡对这些慢性疼痛的治疗，并进一步假设它可能会产生有益的效果，它可能会加强吗啡的止痛作用，并降低疼痛过敏。 建议的商业应用：目前，还没有有效的治疗方法 不影响吗啡止痛能力的吗啡成瘾和毒性。这个 开发一种可以抵消阿片剂的奖励作用的化合物可能会为减少吗啡的滥用潜力提供一种务实的方法，而且选择性地防止吗啡的不良反应的能力将对遭受严重疼痛的患者有重大好处。

DESCRIPTION (provided by applicant): Morphine and other opiate drugs are widely used to treat severe pain but the addiction and side effects they produce often limit their use. The goal of this research is to develop a novel treatment for morphine addiction and toxicity based on an endogenous peptide, glycyl-glutamine (Gly-GIn). Gly-GIn is synthesized in brain from the opioid peptide, beta-endorphin. In preclinical studies, Gly-GIn administration to laboratory animals prevented the respiratory depression and hypotension caused by morphine without compromising morphine's ability to relieve acute pain. The proposed research will test the hypothesis that Gly-GIn inhibits morphine addiction, tolerance and dependence and determine if Gly-GIn influences morphine analgesia in experimental models of chronic pain. Aim 1 will extend preliminary evidence that Gly-GIn pretreatment prevents the acquisition of a conditioned place preference to morphine, an animal model of drug addiction that measures the rewarding or incentive effect of addictive drugs, and determine if Gly-GIn also inhibits the rewarding effects of nicotine. Aim 2 will continue preliminary studies showing that Gly-GIn pretreatment inhibits development of tolerance to morphine analgesia and reduces the severity of physical dependence. Aim 3 will test whether Gly-GIn influences morphine analgesia in experimental models of chronic neuropathic and inflammatory pain. We expect to find that Gly-GIn does not interfere with morphine therapy for these chronic pain conditions and further hypothesize that it may produce beneficial effects, that it may potentiate morphine analgesia and reduce pain hypersensitivity. PROPOSED COMMERCIAL APPLICATION: At present, there are no effective treatments for morphine addiction and toxicity that do not interfere with morphine's ability to relieve pain. The development of a compound that nullifies the rewarding effects of opiates may provide a pragmatic approach for reducing morphine's abuse potential and the ability to selectively prevent morphine's adverse effects would be of significant benefit to patients suffering severe pain.