Our goal is to elucidate the mechanisms by which immune cell-derived endogenous opioids produce analgesia within peripheral inflamed tissue. Our objectives are: 1) to identify exogenous and endogenous agents capable; inhibit pain by releasing opioid peptides within peripheral inflamed tissue in vivo; 2) to elucidate the mechanisms of such release in vitro; and 3) to examine whether opioid peptides are present and active as endogenous analgesics in peripheral human tissue. In vivo experiments assess the alteration of pain thresholds by releasing agents (RA) in rats. In vitro experiments measure the effects of RA on the release of opioid peptides from inflamed an noninflamed tissue and examine the presence of such peptides in human tissue. Clinical studies test the effects of a locally applied opioid antagonist on postoperative pain in patients undergoing arthroscopic surgery. Our overall hypothesis is that, upon stimulation by RA, endogenous opioid peptides can be secreted from immune cells in inflamed tissue and produce analgesia in animals and in man via activation of peripheral opioid receptors.
Specific Aim 1 investigates the effects of exogenous RA on nociceptive thresholds in vivo and on opioid peptide release from immune cell suspensions and tissue homogenates in vitro.
Specific Aim 2 investigates endogenous alterations of nociceptive thresholds in vivo and the mediation of these effects by opioid receptors.
Specific Aim 3 investigates the presence of opioid peptides in human synovial tissue by immunocytochemistry.
Specific Aim 4 examines whether an opioid receptor antagonist, applied locally into the knee joint of patients undergoing arthroscopic knee surgery, will enhance postoperative pain. These studies should provide fundamental new information concerning the mechanisms by which opioids produce analgesia outside the centra nervous system and may contribute to the development of a novel class of peripherally acting analgesics without central opioid side effects such as sedation, nausea, respiratory depression or addiction.
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