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bcox@usuhs.mil
Ph.D., University of London, 1965
B.S., San Diego State College, 1963, 1965
Opiates and endogenous opioids in stress and injury
Opiate drugs are indispensable therapeutic agents in the treatment of severe and chronic pain. These drugs 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, beta-endorphin, and dynorphin. A structurally related peptide, nociceptin (also called orphanin FQ; abbreviated for convenience as N/OFQ) has also been identified. Endogenous opioids and N/OFQ act as neural regulators in many parts of the central and peripheral nervous systems by acting through a family of four closely related G protein coupled receptors; they also influence the immune and endocrine systems. Opioid-regulated neurons show very marked adaptations to chronic opiate drug exposure, resulting in the development of tolerance, physical dependence, and addiction.
Our recent studies have concentrated on N/OFQ. We have shown that strong excitation of nerve cells in culture (mimicking the large release of excitatory amino-acids in brain injury) or after seizures in vivo leads to a marked increase in N/OFQ production in nerve cells, while inflammatory mediators and oxidative stress increase the production of N/OFQ mRNA in glial cells from rat or mouse brain. In living animals, released N/OFQ appears to act locally to render adjacent neurons less likely to survive some types of injury - we have recently demonstrated this in an animal model of Parkinson's disease. N/OFQ and also DYN are also expressed in the amygdala, a brain nucleus implicated in the formation of strongly emotional memories and in post-traumatic stress disorder (PTSD). Here, NOFQ plays a different role in regulation of the association of strongly unpleasant and frightening events with temporally-associated experiences. It has been shown (by others) that injection of N/OFQ directly into the basolateral amygdala up to three hours after an aversive experience impairs memory consolidation, suggesting that N/OFQ or related drugs may be effective in reducing PTSD symptoms.
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