Morphine-induced tolerance in the ileum and colon

吗啡引起的回肠和结肠耐受

• 批准号: 7525435
• 负责人: HAMID I AKBARALI
• 金额: $ 29.9万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7525435
• 关键词: Acute; Animals; Bathing; Brain; Buprenorphine; Chemicals; Chronic; Collaborations; Colon; Constipation; Cyclic ADP-Ribose; Data; Dependence; Development; Drug Prescriptions; Enteral; GRK; Gastrointestinal Physiology; Genus Cola; Goals; In Vitro; Infusion Pumps; Knock-out; Laboratories; Malignant Neoplasms; Measures; Mediating; Molecular; Morphine; Moths; Mus; Muscle; Muscle Contraction; Neurons; Niacinamide; Operative Surgical Procedures; Opioid; Organ; Oxycodone; Pain; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Physical Dependence; Play; Prevention; Procedures; Process; Property; Protein Kinase C; Public Health; Reporting; Research; Role; Ryanodine; Signal Transduction; Testing; Tissues; Western Blotting; Work; chronic pain; experience; gastrointestinal; ileum; in vivo; inhibitor/antagonist; interest; man; mu opioid receptors; prevent; protein expression; receptor

Morphine and other opioids remain the most frequently prescribed drugs for the treatment of moderate to severe pain, including pain due to cancer or surgery. The overall goal of this study is to elucidate the mechanisms of morphine and other opioid-induced tolerance in the ileum and brain but not in the colon which leads to constipation and limits the chronic use of these excellent pain relievers in man. This proposal represents a collaboration of two senior laboratories, one with expertise in gastrointestinal physiology and the other with extensive experience in studying the acute and chronic effects of morphine and other opioids, utilizing molecular, cellular and whole animal approaches. The main hypothesis to be tested is that differences in the cellular signaling properties between the colon and ileum result in morphine-induced tolerance in the ileum but not the colon. We further propose that the ratio of tolerance to various opioids is the same across these tissues. Our preliminary data demonstrate that as marked tolerance develops to the antinociceptive effects of morphine following chronic administration in mice, tolerance does not develop to its constipating effects. The major objective of the work proposed in year 1 is to elucidate whether this difference in tolerance in different tissues observed for morphine is the same for other opioids both in vivo and in vitro. In the second year we propose to further evaluate our interesting finding that nicotinamide, an endogenous CD-38 inhibitor, induces tolerance to morphine in the colon, a phenomenon not previously reported. We will test the hypothesis that the CD-38 pathway prevents tolerance development in the colon and that its blockade by either chemical means or genetically in knock out animals allows tolerance to occur. We propose to investigate whether CD38 in other tissues such as the ileum or brain causes a regulatory effect on the development of tolerance in these tissues as well. Further, we will investigate whether additional steps in the signal transduction process such as the phosphorylation of mu opioid receptors, the activity of protein kinase C and A, GRK alter opioid tolerance development similarly or differently in various tissues. Our preliminary data demonstrate that inhibition of the CD38 pathway by either nicotinamide or 8-bromo cyclic ADPribose results in the induction of tolerance to morphine in the colon. We will test the effects of nictoinamide, ryanodine and cADPribose on tolerance development and on dependence to morphine in the isolated colonic muscle strips and determine if inhibition of the CD38 pathways results in changes in mu receptor phosphorylation in enteric neurons. The long-term major public health implication of this research is the use of this information to develop medications to treat chronic pain that are devoid of constipation. These studies will also increase our understanding of the potential mechanisms in the development of tolerance and ultimately physical dependence to opioids in the brain.

吗啡和其他阿片类药物仍然是最常见的处方药，用于治疗中度至严重疼痛，包括癌症或手术引起的疼痛。这项研究的总体目的是阐明吗啡和其他阿片类药物诱导的回肠和大脑的耐受性的机制，而不是在结肠中导致便秘的结肠，并限制了这些出色的止痛药在人中的长期使用。该提案代表了两个高级实验室的合作，一个是胃肠道生理学专业知识，另一个在研究吗啡和其他阿片类药物的急性和慢性作用方面具有丰富的经验，利用分子，细胞和全动物方法。要测试的主要假设是结肠和回肠之间细胞信号传导特性的差异导致吗啡诱导的回肠耐受性，而不是结肠。我们进一步提出，在这些组织中，耐受性与各种阿片类药物的比率相同。我们的初步数据表明，随着慢性给药后，明显的耐受性会发展出对小鼠长期给药后吗啡的抗伤害感受作用，因此耐受性不会发展到其便携式作用上。第1年提出的工作的主要目的是阐明在体内和体外其他阿片类药物中观察到的吗啡的不同组织中这种耐受性的差异是否相同。在第二年，我们建议进一步评估我们有趣的发现，即烟酰胺是一种内源性CD-38抑制剂，可诱导结肠中吗啡的耐受性，这是先前没有报道的现象。我们将检验以下假设：CD-38途径可防止结肠的公差发展，并且其通过化学方法或遗传敲除动物的封锁可以实现耐受性。我们建议研究其他组织中的CD38（例如回肠或大脑）是否也会对这些组织的耐受性发展产生调节作用。此外，我们将研究信号转导过程中的其他步骤，例如MU阿片受体的磷酸化，蛋白激酶C和A的活性是否在各种组织中均类似或不同。我们的初步数据表明，烟酰胺或8-Bromo循环adpribose抑制CD38途径会导致结肠中吗啡的耐受性。我们将测试米氧胺，瑞亚氨甲氨酸和cadpribose对分离的结肠肌肉条中耐受性发展以及对吗啡的依赖性的影响，并确定抑制CD38途径是否导致肠神经元中的MU受体磷酸化的变化。这项研究的长期主要公共卫生含义是使用该信息来开发药物治疗缺乏便秘的慢性疼痛。这些研究还将增加我们对耐受性发展的潜在机制以及最终对大脑阿片类药物的依赖性的理解。