Role of peripheral N-methyl-D-aspartate (NMDA) receptors in visceral nociception in rats

(Background & Aims) under bar: N-methyl-D-aspartate (NMDA) receptors are li gand-gated ion channels that have an important role in long-term potentiati on and memory processing in the central nervous system. The aims in this st udy were to determine whether NMDA receptors are expressed in the periphera l nervous system and identify their role in mediating behavioral pain respo nses to colonic distention in the normal gut, (Methods and Results) under b ar: Immunohistochemical localization of the NR1 subunit showed that NMDA re ceptors are expressed on the cell bodies and peripheral terminals of primar y afferent nerves innervating the colon. Dorsal root ganglia neurons retrog radely labeled from the colon in short-term culture responded to addition o f NMDA with increased intracellular [Ca2+]. Activation of peripheral NMDA r eceptors in colonic tissue sections caused Ca2+-dependent release of the pr oinflammatory neuropeptides, calcitonin gene-related peptide and substance P. Behavioral pain responses to noxious mechanical stimulation were inhibit ed in a reversible, dose-dependent manner by intravenous administration of memantine, a noncompetitive antagonist of the NMDA receptor. Single fiber r ecordings of decentralized pelvic nerves showed that colorectal distention responsive afferent nerve activity was inhibited by memantine, (Conclusions ) under bar: Peripheral NMDA receptors are important in normal visceral pai n transmission, and may provide a novel mechanism for development of periph eral sensitization and visceral hyperalgesia.