Nitric oxide (NO) may play an important role in central and peripheral nociceptive processes. However, its contribution to peripheral antinociception is still not clear. In the present study, we investigated the effect of peripherally administered FK409, a spontaneous NO releaser, and its interaction with peripheral morphine analgesia during the rat formalin test. Intraplantar injection of formalin resulted in a biphasic appearance of flinching behavior (Phase 1 = 0-9 min, Phase 2 = 10-60 min). First, an intraplantar injection of FK409 was given 5 min before the formalin injection to test for its effect alone. In the next experiment, morphine was administered first, followed 15 min later by the phosphate buffer (pH 6.0) or FK409 injection, and 5 min later by the formalin injection. FK409 alone had no effect on the number of flinches in either phase. However, when administered after intraplantar morphine, FK409 dose-dependently depressed the agitation behavior in both phases. It shifted the dose-response curve of morphine to the left. Naloxone and carboxy-PTIO (an NO scavenger) each reversed the suppressant effect of morphine and FK409 given together. These data suggest that NO enhances the analgesic effect of peripherally administered morphine in the formalin test.
Implications: Peripherally administered nitric oxide itself has no analgesic effect, but it enhances the analgesic effects of peripherally administered morphine during inflammation induced by paw formalin injection in the rat.