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 report ed to be involved in the mechanisms that underlie thermal hyperalgesia produced by the intraplantar injection of carrageenan. As NMDA-mediat ed thermal hyperalgesia produced in models of acute and persistent pai n have been reported to involve production of nitric oxide, we examine d the role of nitric oxide in both the development and maintenance of the thermal hyperalgesia produced by the intraplantar injection of car rageenan. In addition, we examined the role of nitric oxide in the mai ntenance of the mechanical hyperalgesia produced by intraplantar injec tion of carrageenan. Prior to the intraplantar injection of carrageena n (2 mg in 100 mu l) there was no significant difference in thermal wi thdrawal latencies or mechanical withdrawal thresholds between the lef t and right hindpaws. Three hours after injection of carrageenan into the left hindpaw, rats showed evidence of a significantly faster therm al withdrawal latency and lower mechanical withdrawal threshold of the left hindpaw compared to the right hindpaw. In addition, the left hin dpaw was significantly increased in size (diameter) compared with the right hindpaw. In these same rats, the intrathecal administration of s aline, N-G-nitro-L-arginine methyl ester (L-NAME; 2-200 nmol) or the i nactive enantiomer, N-G-nitro-D-arginine methyl ester (D-NAME; 200 nmo l) did not produce any significant change in thermal nociceptive withd rawal 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 t o 3 h. In contrast, neither L-NAME, D-NAME nor saline affected the mec hanical hyperalgesia or the edema produced by the intraplantar injecti on of carrageenan. These data suggest that the production of nitric ox ide, 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 demon strated that nitric oxide was involved in the maintenance of thermal b ut not mechanical hyperalgesia, an additional series of experiments wa s conducted to examine the role of nitric oxide in the development of the thermal hyperalgesia produced by the intraplantar injection of car rageenan. Administration of L-NAME (2-200 nmol), but not D-NAME (200 n mol) 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, blo cking the production of nitric oxide resulted in a delay in the onset of thermal hyperalgesia, but did not prevent its development. Collecti vely, these data are consistent with the hypotheses that the maintenan ce of thermal but not mechanical hyperalgesia is dependent on producti on of nitric oxide, and that the development of thermal hyperalgesia i nvolves the production of nitric oxide.