Role of Glutamate in Opiate Tolerance and Sensitization

描述(由申请人提供)： 这项研究的总体目标是利用行为药理学方法探索阿片类药物耐受性和敏化的发展。鸦片类药物，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。这些药物也是广泛自我管理的，因此是重要的滥用药物。长期使用鸦片类药物治疗会导致众所周知的后果，包括耐受性，即长期使用药物的效果降低，以及致敏，即长期使用药物的效果增加。这些现象在使用阿片类药物治疗疼痛和发展阿片成瘾两方面都很重要。 最近的实验表明，谷氨酸是大脑中的一种兴奋性神经递质，可能参与了阿片类药物长期治疗的后果，包括耐受性和敏化。然而，为了更好地了解谷氨酸在阿片类药物作用中的作用，有必要进行进一步的研究。本研究将探讨AMPA受体(谷氨酸受体的一种)或谷氨酸释放是否与阿片类药物耐受和敏化有关。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敏化发展的能力来实现。阿片类药物的止痛作用和运动作用将是这些研究的行为终点。这项工作将扩展首席调查员和其他人之前关于谷氨酸在阿片剂诱导的行为和神经可塑性中的作用的研究。这些研究的结果将在理论上具有重要意义，对于了解参与阿片类药物作用的神经递质系统，以及理解谷氨酸药物在治疗疼痛和阿片成瘾方面的潜力具有实际意义。

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.