The objectives of this project are 1) to evaluate the neuroendocrine responses to surgical stress and inflammation, 2) to determine the analgesic and anti-inflammatory effects of prototype and novel drugs which alter either the synthesis or the receptor activation of neuroendocrine mediators in an established animal model of inflammation, and 3) to evaluate the clinical utility of these novel drugs in controlled clinical trials. This year, we have extended our research on factors regulating the pituitary release of beta-endorphin under conditions of stress. Subjects undergoing the removal of impacted third molars received epinephrine in conjunction with local anesthesia which resulted in a 30-fold increase in circulating epinephrine levels. Elevated epinephrine levels significantly reduced beta-endorphin levels in response to surgical stress in comparison to a control group which did not receive epinephrine. These results do not support the hypothesis of a stimulatory effect of epinephrine on endorphin release and, instead, suggest that an inhibitory relationship may exist in humans experiencing stress. We have also extended our research on bradykinin with the use of microdialysis probes which permit accurate measurement of the levels of inflammatory mediators in inflamed tissue. In oral surgery patients, tissue levels of iBK increased nearly 10-fold over a 4 hour observation period. The peak in tissue concentrations of iBK precedes the peak in pain report and the two factors are significantly correlated. Blockade of bradykinin receptors with a bradykinin antagonist in a parallel study in rats significantly blocked hyperalgesia, hyperthermia, and edema. These observations suggest that bradykinin release is involved in clinical pain and that blockade of its release or its receptor mediated actions may result in analgesia and other antiinflammatory effects.
