Role of Glutamate in Opiate Tolerance and Sensitization

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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.