Role of Glutamate in Opiate Tolerance and Sensitization

谷氨酸在阿片类药物耐受性和致敏中的作用

• 批准号: 6952954
• 负责人: KEITH A TRUJILLO
• 金额: $ 22.2万
• 依托单位: CALIFORNIA STATE UNIVERSITY SAN MARCOS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6952954
• 关键词: AMPA receptors; NMDA receptors; analgesia; anticonvulsants; behavior test; behavioral /social science research tag; benzodiazepines; central nervous system depressants; drug abuse; drug habituation; drug tolerance; glutamate transporter; glutamates; laboratory rat; morphine; muscle relaxants; neural plasticity; neuropharmacology; neurotransmitter antagonist; neurotransmitter transport; opiate alkaloid; psychomotor function; psychopharmacology

DESCRIPTION (provided by applicant): The global aim of this research is to explore the development of opiate tolerance and sensitization, using a behavioral pharmacological approach. Opiates, such as morphine, are very potent pain relievers and are therefore the drugs of choice for the treatment of severe or chronic pain. These drugs are also widely self-administered and are therefore important drugs of abuse. Long-term treatment with opiates leads to well-known consequences, including tolerance, which is a decrease in an effect of a drug with chronic use, and sensitization, which is an increase in an effect of a drug with chronic use. These phenomena are important in both the use of opiates for the treatment of pain and in the development of opiate addiction. Recent experiments suggest that glutamate, an excitatory neurotransmitter in the brain, may be involved in the consequences of long-term treatment with opiates, including tolerance and sensitization. However, further research is necessary to better understand the role of glutamate in opiate effects. The present research will examine whether AMPA receptors (a type of glutamate receptor) or glutamate release may be involved in opiate tolerance and sensitization. This will be achieved by exploring the ability of AMPA receptor antagonists and glutamate release inhibitors to alter the development of opiate tolerance and sensitization in rats. Analgesic effects and locomotor effects of opiates will be the behavioral end-points for these studies. This work will extend previous research by the Principal Investigator and others on the role of glutamate in opiate-induced behavioral and neural plasticity. The results of these studies will be of theoretical importance, in understanding the neurotransmitter systems involved in the effects of opiates, and of practical importance in understanding the potential for glutamate drugs in the treatment of pain and opiate addiction.

描述（由申请人提供）： 这项研究的全球目的是使用行为药理学方法探索鸦片耐受性和敏化的发展。阿片类药物（例如吗啡）是非常有效的止痛药，因此是治疗严重或慢性疼痛的首选药物。这些药物也被广泛自我管理，因此是滥用的重要药物。长期用阿片类药物的长期治疗会导致众所周知的后果，包括耐受性，这是慢性使用药物的作用和敏化作用的降低，这是药物对慢性使用的效果的增加。这些现象在使用阿片类药物治疗疼痛和鸦片成瘾的发展方面都很重要。 最近的实验表明，谷氨酸是大脑中的兴奋性神经递质，可能参与了用鸦片治疗的长期治疗的后果，包括耐受性和敏化。但是，必须进一步研究以更好地了解谷氨酸在阿片类药物效应中的作用。本研究将检查AMPA受体（一种类型的谷氨酸受体）或谷氨酸释放是否可能参与鸦片耐受性和敏化。这将通过探索AMPA受体拮抗剂和谷氨酸释放抑制剂改变大鼠鸦片耐受性和敏化的发展的能力来实现。阿片类药物的镇痛作用和运动作用将是这些研究的行为终点。这项工作将扩大主要研究者和其他人对谷氨酸在阿片类鸦片诱导的行为和神经可塑性中的作用的研究。这些研究的结果将具有理论上的重要性，以理解涉及阿片类药物影响的神经递质系统，以及在理解谷氨酸药物治疗疼痛和鸦片成瘾方面的潜力方面的实际重要性。