Comparison of the Antinociceptive Effects of Pre- and Posttreatment with Intrathecal Morphine and MK801, an NMDA Antagonist, on the Formalin Test in the Rat
Current thinking emphasizes that protracted small afferent input can evoke mechanisms that mediate a significant potentiation of spinal nociceptive processing and that this facilitory component has a unique pharmacology. To investigate the behavioral parallels of this spinal facilitation, we evaluated the effects of pre- and posttreatment of intrathecal morphine (µ agonist) and MK801 (N-methyl-D-aspartate [NMDA] antagonist) on the formalin test. Intraplantar formalin resulted in a biphasic appearance of flinching behavior (phase 1= 0–5 min; phase 2 = 10–60 min). Morphine and MK801 were administered intrathecally 15 min before formalin injection in the pretreatment study and 9 min after formalin injection in the posttreatment study. Pretreatment with intrathecal morphine produced comparable dose-dependent suppressions of the phase 1 and phase 2 behaviors (ED50 = 0.5 µg [95% CI = 0.3–0.9] and 0.3 µg [95% CI = 0.1–0.7], respectively). Posttreatment with morphine also resulted in comparable suppression of the phase 2 response (ED50 = 0.2 µg [95% CI = 0.1–0.3]). At the highest dose of intrathecal morphine (10 µg), an almost complete suppression of formalin-evoked behavior was observed. Pretreatment with MK801 inhibited the second-phase response more strongly than the first-phase response (ED50 = 1.6 µg [95% CI = 0.5–5.7] vs. 0.1 µg [95% CI = 0.3–0.4], respectively). In contrast, posttreatment with the highest dose of MK801 had no effect on the phase 2 response. These data yield the hypothesis that the focal stimulation provided by the presence of subcutaneous formalin exerts 1) a direct excitatory effect evoking clearly defined pain behavior that is independent of the spinal NMDA sites but subject to opioid modulation and 2) a second facilitated component, in which the acute afferent barrage serves to up-regulate the organized response of the animal to an already noxious stimulus. This study suggests that the NMDA site is required to initiate this facilitory component but not to sustain it.