THE ROLE OF NITRIC-OXIDE IN THE DEVELOPMENT AND MAINTENANCE OF THE HYPERALGESIA PRODUCED BY INTRAPLANTAR INJECTION OF CARRAGEENAN IN THE RAT

Activation of the N-methyl-D-aspartate (NMDA) receptor has been reported to be involved in the mechanisms that underlie thermal hyperalgesia produced by the intraplantar injection of carrageenan. As NMDA-mediated thermal hyperalgesia produced in models of acute and persistent pain have been reported to involve production of nitric oxide, we examined the role of nitric oxide in both the development and maintenance of the thermal hyperalgesia produced by the intraplantar injection of carrageenan. In addition, we examined the role of nitric oxide in the maintenance of the mechanical hyperalgesia produced by intraplantar injection of carrageenan. Prior to the intraplantar injection of carrageenan (2 mg in 100 mu l) there was no significant difference in thermal withdrawal latencies or mechanical withdrawal thresholds between the left and right hindpaws. Three hours after injection of carrageenan into the left hindpaw, rats showed evidence of a significantly faster thermal withdrawal latency and lower mechanical withdrawal threshold of the left hindpaw compared to the right hindpaw. In addition, the left hindpaw was significantly increased in size (diameter) compared with the right hindpaw. In these same rats, the intrathecal administration of saline, N-G-nitro-L-arginine methyl ester (L-NAME; 2-200 nmol) or the inactive enantiomer, N-G-nitro-D-arginine methyl ester (D-NAME; 200 nmol) did not produce any significant change in thermal nociceptive withdrawal latencies in the non-injected paw. However, administration of L-NAME (2-200 nmol), but not saline or D-NAME, produced a dose dependent and reversible block of the thermal hyperalgesia for a period of up to 3 h. In contrast, neither L-NAME, D-NAME nor saline affected the mechanical hyperalgesia or the edema produced by the intraplantar injection of carrageenan. These data suggest that the production of nitric oxide, in the spinal cord, is involved in the maintenance of the thermal hyperalgesia, but not the mechanical hyperalgesia or the inflammation produced in this model of persistent pain. As these experiments demonstrated that nitric oxide was involved in the maintenance of thermal but not mechanical hyperalgesia, an additional series of experiments was conducted to examine the role of nitric oxide in the development of the thermal hyperalgesia produced by the intraplantar injection of carrageenan. Administration of L-NAME (2-200 nmol), but not D-NAME (200 nmol) or saline, 30 min prior to carrageenan and again at 90 min after carrageenan produced a delay in the onset of the thermal hyperalgesia, consistent with the time course of the effect of L-NAME. That is, blocking the production of nitric oxide resulted in a delay in the onset of thermal hyperalgesia, but did not prevent its development. Collectively, these data are consistent with the hypotheses that the maintenance of thermal but not mechanical hyperalgesia is dependent on production of nitric oxide, and that the development of thermal hyperalgesia involves the production of nitric oxide.