ROLE OF NMDA RECEPTORS IN ACUTE AND CHRONIC BEHAVIORAL ACTIONS OF OPIATES

本研究的目的是探索兴奋性氨基酸系统在阿片类药物急性和慢性作用中的潜在作用。吗啡等阿片类药物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。长期使用阿片类药物会导致三种众所周知的后果：耐受性，这是长期使用药物的效果下降;致敏性，这是长期使用药物的效果增加，因此不使用药物会导致令人不快的戒断症状。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，一种兴奋性氨基酸受体，即N-甲基-D-天冬氨酸（NMDA）受体，可能在阿片类药物长期治疗的后果中发挥核心作用，包括耐受性、致敏性和身体依赖性。此外，越来越多的证据表明，这种受体也可能参与阿片类药物的某些急性作用，包括镇痛和促肾上腺皮质激素活性。然而，需要进一步的研究来更充分地了解NMDA受体在阿片类药物急性和慢性效应中的作用。本提案中概述的研究将检查NMDA受体药物改变阿片类药物对大鼠的急性镇痛和急性运动效应的能力，以及长期给予阿片类药物的后果，包括耐受性、致敏性和身体依赖性。如果NMDA受体确实参与了这些阿片类药物引起的行为，那么阻断NMDA受体的药物应该可以改变吗啡和其他阿片类药物的急性和慢性效应。这些研究的结果将是理论上的重要性，对更好地了解阿片类药物的关键行为影响所涉及的神经递质系统。此外，这些结果可能是临床相关的，阐明了潜在的效用的NMDA受体拮抗剂在治疗疼痛和阿片类药物成瘾。

The global aim of this research is to explore the potential role of excitatory amino acid systems in acute and chronic actions of opiates. 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 three well-known consequences: tolerance, which is a decrease in the effect of a drug with chronic use; sensitization, which is an increase in the effect of a drug with chronic use, such that absence of the drug results in an unpleasant withdrawal symptom. 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 an excitatory amino acid receptor, known as the N-methyl-D-aspartate (NMDA) receptor, may have a central role in the consequences of long-term treatment with opiates, including tolerance, sensitization and physical dependence. Additionally, there is increasing evidence that this receptor may also be involved in selected acute actions of opiates, including analgesia and locomoter activity. Further research is necessary, however, to more fully understand the role of NMDA receptors in acute and chronic effects of opiates. The studies outlined in this proposal will examine the ability of NMDA receptor drugs to alter the acute analgesic and the acute locomotor effects of opiates in rats, as well as the consequences of long- term opiate administration, including tolerance, sensitization and physical dependence. If NMDA receptors are indeed involved in these opiate- elicited behaviors, then drugs that block NMDA receptors should alter the acute and chronic effects of morphine and other opiates. The results of these studies will be of theoretical importance, toward a better understanding of the neurotransmitter systems involved in critical behavioral effects of opiates. Moreover, these results may be of clinical relevance by elucidating the potential utility of NMDA receptor antagonists in the treatment of pain and opiate addiction.