Aging Confers an Increase in Sensitivity and Sensitization to Pain and Results in Shifts of Spinal NR1 expression

Purpose: Many elderly experience inadequate postoperative pain relief resulting in increased morbidity and mortality. Several experimental models of postoperative pain have been developed but none were adapted to study the effects of aging on the postoperative pain. Review of literature explored current knowledge of postoperative pain models and identified several models suitable for aging studies. A unique model of postoperative pain, the dorsal hairy skin incision model, was modified and adopted for aged rats. Using this model, we tested two hypotheses: a) aged rats will exhibit similar intensity but longer duration of postincision hyperalgesia compared to young rats and b) spinal cord NR1 expression will increase in response to nociceptive stimulation and that age-related differences in magnitude of NR1 expression will be evident. Methods: In study I, young (5-7 months old) and aged (22-23 months old) male Fischer 344 rats were exposed to nociceptive testing with von Frey filaments and the cutaneous trunci muscle reflex was measured. For each stimulation, a graded response of 0, 0.5, or 1, for no reflex, a small reflex, or vigorous reflex, respectively was recorded. After baseline testing, a 2 cm incision was made through the dorsal skin followed by skin closure and recovery. Subsequently, rats were tested at 3 hours, 6 hours, and on postoperative days (POD) 1, 3, 6, 10, and 14. In study II, young (4-6 months old) and aged (19-21 months old) male Fischer 344 rats were subjected to three sessions of mechanical nociceptive stimulus. After testing, spinal cords were harvested for western blot analysis of NR1 expression. Results: In study I, aged rats had greater baseline graded responses to nociceptive stimuli. After incision, young rats developed primary allodynia lasting until POD 3 and primary hyperalgesia until POD 8. Aged rats did not develop allodynia or primary hyperalgesia. Neither group developed secondary hyperalgesia. Aged rats demonstrated greater sensitivity to baseline nociceptive testing and greater maximal graded responses to repetitive testing sessions. In young rats, nociceptive stimulation resulted in a significant increase in NR1 expression. Increased NR1 expression in young tested rats positively correlated with an increase in graded response for one of 18 session/region/force categories tested. There was no increase in spinal cord NR1 expression in aged rats in response to nociceptive stimulation. Low NR1 expression in aged tested rats negatively correlated with an increase in graded response for 9 of 18 session/region/force categories tested. Conclusions: An experimental rat model to study effects of age on postoperative pain is presented. Age has a profound impact on the pre- and postoperative periods. Aged rats differ significantly from young rats in sensitivity and maximal graded response to acute incisional pain. Young rats exposed to mechanical punctate nociceptive stimuli experienced increased NR1 expression which positively correlated with an increase in graded response. In contrast, aged rats with decreased NR1 expression negatively correlated with an increased graded response. Lower sensitivity and maximal graded responses in the young rats reflect an intact endogenous modulatory pain pathway. Greater sensitivity and maximal graded responses in the aged rats reflect impairment of descending modulatory pain pathways.