The display of naloxone reversible analgesia in mice subjected to a biologically relevant stressor such as defeat by another mouse indicates a functional role of endogenous opioids in response to stress. The unique aspect of this model of stress analgesia is that upon repeated exposure to defeat, these mice show the development of tolerance, cross-tolerance to morphine, and physical dependence. The purpose of this project is: 1) to identify the opiate receptor subtypes and opioid peptides which mediate the acute analgesic response to stress, 2) to attempt to relate the development of tolerance, cross-tolerance and physicl dependence phenomena to changes in receptor binding and/or prolonged changes in opioid peptide release, and 3) to assess the effects of chronic defeat stress on response to other drugs. Antagonists which are relatively specific for mu, kappa, and delta receptors will be tested for their potential to block defeat analgesia. The effect of depletion of beta-endorphin by neonatal MSG treatment will also be assessed. HPLC and radioimmunoassay techniques will be used to measure release of enkephalins and beta-endorphin in response to acute and chronic defeat stress. Receptor binding studies will be used to look for changes in number or affinity of mu, kappa, and delta receptors in different brain regions following chronic defeat. The responsiveness of chronically defeated mice to the stimulant and stereotypy-producing effects of drugs such as amphetamine will be tested. These studies should provide new insights into the interaction of stress and endogenous opioid mechanisms.
