Effect of cyclooxygenase-1 inhibition in postoperative pain is developmentally regulated.

THE paw incision in the rat has been established as a reproducible model to study acute postoperative pain in adult animals and during development. Age-dependent differences in behavioral responses using the paw incision model have been established by showing that 2-week-old animals recover more rapidly than older animals after paw incision as measured by withdrawal threshold to mechanical stimulation. The etiology of this difference has not been studied. One possible explanation is that similar tissue injury results in differences in the inflammatory response as a function of development. The production of cytokines is one marker of inflammation and developmental differences in production of tumor necrosis factor and interleukin 1 have been found to be developmentally regulated after surgical tissue trauma. However, the role of other inflammatory mediators in developmental responses to pain is unknown. Cyclooxygenase (COX) enzymes and their products represent targets of intense interest in pain sensation and treatment. COX enzymes and prostaglandins have been studied extensively during the past 30 yr to determine their roles in the inflammatory response. During the past 10 yr, COX-2 has been given particular attention and has led to the development of selective compounds to maximize pain relief while reducing the negative effects caused by nonselective inhibition of COX isozymes. COX-1 and COX-2 are constitutively expressed in the rat spinal cord, and intrathecal administration of COX-2 inhibitors reduces mechanical allodynia caused by peripheral inflammation from complete injection of Freund’s adjuvant. COX-2 has been shown to be expressed in the spinal cord after paw incision, but this expression only occurs for a very short time after the injury. However, Zhu and Eisenach recently showed that intrathecal injection of the selective COX-2 inhibitor NS-398 had minimal analgesic effects in an incisional model of postoperative pain. In contrast, spinal COX-1 inhibition, by intrathecal injection of the selective compound SC560, produced a dose-dependent decrease in mechanical allodynia in adult animals after incisional surgery. The authors also showed that COX-1 expression in the spinal cord increases in response to paw incision. COX-1 is also up-regulated in the spinal cord of rats in other models of pain, such as partial sciatic nerve ligation and L5–L6 spinal nerve ligation. These findings suggest that COX-1 plays a potentially important role in the inflammatory response to peripheral tissue and nerve injury in mature rats. The role of COX-1 in young animals and potential age-dependent behavioral responses to acute postoperative pain, however, have not been characterized. In this study, we hypothesize that development plays a role in age-specific behavioral responses to COX-1 inhibition as measured using response to mechanical and thermal stimuli.