The goal of this work is to conduct a systematic study of the ability of centrally acting analgesic agents to produce analgesia by actions on the peripheral nervous system. The study is designed to provide answers to three questions: (1) What peripheral receptor systems among those that modulate pain centrally are capable of producing peripheral analgesia? (2) Is the peripheral analgesia produced by the systems identified as efficacious in the periphery greater or less than the analgesia produced by those same systems within the spinal cord? (3) Are there additive or synergistic peripheral interactions between those systems and between them and low doses of local anesthetics? Studies will be carried out in a behavioral model developed by the investigator which permits testing in both a normal and a hyperalgesic state. A thermal injury to one hind foot is created in a rat under general anesthesia and withdrawal latency to a thermal stimulus tested two hours later. If hyperalgesia, considered as a difference >1.5 sec in withdrawal latency between injured and uninjured paws, is present, the animal is used for analgesia testing twenty-four hours later. Hyperalgesia is again documented at this time. Drug injection into one paw is carried out under halothane anesthesia, which is then discontinued, and latencies to withdrawal measured every 15 minutes after the animal awakens. Latencies of treated and untreated paws are compared to detect systemic versus local analgesic effects. Agents to be tested include agonists at cholinergic, opiate and adenosine A1 receptors, and antagonists at excitatory amino acid, NK1 and adenosine A2 receptors. Attempts will be made to obtain and test new compounds that do not cross the blood-brain barrier.
