Role of Glutamate in Opiate Tolerance and Sensitization

描述（由申请人提供）： 本研究的全球目标是使用行为药理学方法探索阿片类药物耐受性和致敏性的发展。阿片类药物，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。这些药物也广泛地自我给药，因此是重要的滥用药物。长期使用阿片剂治疗会导致众所周知的后果，包括耐受性和致敏性，耐受性是指长期使用药物的效果减弱，致敏性是指长期使用药物的效果增强。这些现象在使用阿片类药物治疗疼痛和阿片类药物成瘾的发展中都很重要。 最近的实验表明，谷氨酸，大脑中的兴奋性神经递质，可能参与长期阿片类药物治疗的后果，包括耐受性和致敏性。然而，需要进一步的研究来更好地了解谷氨酸在阿片作用中的作用。本研究将探讨AMPA受体（一种谷氨酸受体）或谷氨酸释放是否可能参与阿片耐受和致敏。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阿片耐受性和致敏性发展的能力来实现。阿片类药物的镇痛效应和运动效应将是这些研究的行为终点。这项工作将扩展首席研究员和其他人先前关于谷氨酸在阿片诱导的行为和神经可塑性中的作用的研究。这些研究的结果将是理论上的重要性，在了解阿片类药物的影响所涉及的神经递质系统，并在了解潜在的谷氨酸药物在治疗疼痛和阿片类药物成瘾的实际重要性。

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.