NMDA receptor antagonists attenuate noxious and nonnoxious colorectal distention-induced Fos expression in the spinal cord and the visceromotor reflex

Abstract

In the present three-part study, the effects of intrathecally administered N-methyl- D-aspartate (NMDA) receptor antagonists on responses to noxious and innocuous colorectal distention (CRD) were examined. In the first part, a passive-avoidance paradigm was used to confirm that 80 mm Hg CRD is a noxious stimulus since it produced avoidance behavior. Acquisition of this behavior was blocked by the NMDA receptor antagonist D(−)-2-amino-5-phosphonopetanoic acid (APV, 60 nmol, intrathecal). In contrast, 20 mm Hg CRD is an innocuous stimulus since there was no difference in the behavior of these animals compared to nondistended controls. In the second part, the effects of the NMDA receptor antagonist dizocilpine maleate (MK-801, 0–100 nmol, intrathecal) on CRD-induced Fos expression in the lumbosacral spinal cord were examined. Noxious and innocuous CRD induced 98±4 and 50±2 Fos labeled cells per section per side of the spinal cord, respectively. MK-801 dose-dependently attenuated noxious CRD-induced Fos. Compared to saline, the peak attenuation was 55%. Innocuous CRD-induced Fos was attenuated by 36% following 100 nmol MK-801. In the third part, the effects of APV (0–240 nmol, intrathecal) on the visceromotor reflex were examined. APV dose-dependently attenuated the visceromotor reflex to graded intensities of CRD that went from the innocuous into the noxious range. In separate animals that only received innocuous stimulation, APV dose-dependently attenuated the visceromotor reflex. The magnitude of attenuation was similar for both stimulus paradigms. These data expand upon our previous dorsal horn neuronal recordings which showed that spinal NMDA receptors partially mediate the processing of both noxious and innocuous colorectal stimuli. They further underscore a difference from somatic tissue in the role of NMDA receptors in processing acute or transient visceral stimuli in the absence of tissue injury.