Historically, analgesic pharmacologists have studied animal models of acute pain but have been reluctant or unable to develop and evaluate analgesics in models of chronic pain. The rat paw-formalin procedure represents one of the few pain tests that gives steady (tonic) pain associated with minor tissue damage i.e. pain that may be neurochemically and neurophysiologically different from brief (phasic) pain associated with conventional hot plate and tail flick tests. The overall aim of the proposal is to characterize, under rigorously standardized conditions, important opioids (e.g. buprenorphine, sufentanil), peptides (e.g. neurotensin, cholecystokinin octapeptide), opioid peptides (e.g. dynorphin A) and critical experimental compounds (e.g. U-50,488H) in the formalin model. Test compounds will be studied in this procedure and compared with activities in an untreated paw pressure test of acute pain. Constipation - the second classical effect of opiates - will be measured for each compound in the rat colonic antitransit test and related to corresponding analgesic activities. Test agents will be compared in both endpoints (analgesia and transit) after intrathecal, intracerebroventricular, subcutaneous and, where appropriate, intraperiaqueductal gray administration. This approach will give valuable information on locus of action. Tolerance development will be assessed since tolerance/crosstolerance experiments have traditionally been helpful in the subclassification of analgesics. Additionally, the challenging contention that tolerance to opiates does not occur under chronic pain conditions, will be investigated.
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