Uniformed Services University of the Health Sciences
Department of Pharmacology
4301 Jones Bridge Road
Bethesda, Maryland 20814-4799
Phone: (301) 295-3223
FAX: (301) 295-3220
Phone: (301) 295-3260
Opiate drugs are indispensable therapeutic agents in the treatment of severe and chronic pain. They act at receptors normally utilized by members of a family of naturally occurring peptides, the endogenous opioid peptides. Several peptides fall into this group, including the enkephalins, ?-endorphin, and dynorphin. A structurally related peptide, nociceptin (also called orphanin FQ; abbreviated N/OFQ) was identified in 1995. Endogenous opioids and N/OFQ act through a set of specific receptors as neural regulators in many parts of the central and peripheral nervous systems. The regulatory role of opioid receptors in pain pathways accounts for the potent analgesic actions of opiate drugs such as morphine. These peptides and their receptors are also important regulators of the central pathways mediating behavioral reinforcement, and thus play a role in the reward mechanisms associated with satisfaction of our needs for fluid replacement, maintained nutrition and reproduction of the species. This makes opioid receptors participants in drug addictions not only for opiate drugs such as heroin but also in the reinforcing actions of other drugs of abuse such as ethanol, amphetamines, cocaine and marijuana. Opioid-regulated neurons show very marked adaptations to chronic opiate drug exposure, resulting in the development of tolerance, physical dependence, and addiction.
In recent studies, we have found that the expression of enkephalins, N/OFQ, their precursor peptides and their mRNAs are significantly increased in neurons and/or glial cells following neuronal activation or exposure to cytokines, to oxidative stress, or ischemia and re-perfusion. In neurons, expression of these peptides is increased by neuronal depolarization or elevation of intracellular calcium. It is not surprising, therefore, that N/OFQ levels are increased in brain by mechanical injury, seizures or neurotoxic agents including those inducing symptoms closely reminiscent in Parkinson?s Disease. We are now studying the expression and functions of N/OFQ and other opioids in regulating central dopamine neurons in experimental models of Parkinson's Disease, or after seizure generation.