The question of whether or not infants experience pain has been historically controversial but there is no longer any question that they do feel pain and that failure to alleviate pain for serious medical problems increases morbidity and mortality. The question of how to treat pain in infants is particularly difficult for the clinician. Opiate drugs are often the analgesics of choice yet act differently in the infant than in the adult because opioid systems are still maturing during the perinatal period. This is a growing problem given the increased survival rate of premature infants. Pain due to inflammation and infection are major clinical problems for full term and premature neonates and for children. Classically, opiates have been known to induce analgesia by acting on the central nervous system. More recently it has become apparent that they can also act in peripheral tissue to alleviate pain, and peripherally acting opiates are most effective in inflamed tissue. Opiates likely produce their antinociceptive actions in inflamed tissue by actions on nerve cells and possibly in interaction with the immune system. Furthermore, structural changes in inflamed tissue may allow drugs to access nerves that are normally unavailable in non-inflamed tissue. A clinical advantage of peripherally induced analgesics is that many of the unwanted side effects, such as sedation and mental confusion, may be avoidable. This would be particularly important advantage for infants and children. But all studies on the efficacy of peripheral opiates in inflammatory pain have been conducted in mature animals despite the prevalence of inflammation in infant patients and the difficulties of administering opiates to infants and children. The effects of peripherally administered opiates in the infant patient are certain to differ from those in adult patient given the immaturity of the nervous system, the immune system and the structure of peripheral tissues in the young. The general aims of this application are to examine the development of analgesia induced by peripherally administered opiates. Specifically, it is proposed to study, in a rat model, the development of the inflammatory process with special attention to its effects on pain threshold; the development of opiate induced antinociception in inflamed and non-inflamed tissue; and upregulation of opioid peptides and receptors induced by inflammation in neurons and immune cells. This will provide important information about the process of inflammation and opiate induced analgesia in damage tissue during normal development.
