Role of glutamate receptors and nitric oxide in the rostral ventromedial medulla in visceral hyperalgesia.
The present study was undertaken to examine the involvement of descending pain modulatory systems from the brainstem rostral ventromedial medulla (RVM) in modulating visceral hyperalgesia produced by intracolonic instillation of zymosan. Three hours after intracolonic zymosan, the visceromotor response (VMR) to noxious colorectal distension (CRD, 80 mmHg, 20s) was increased significantly. This hyperalgesia was attenuated in a dose-dependent manner by the selective NMDA receptor antagonist APV (10-30 fmol, 1 microl) microinjected into the RVM. The hyperalgesia was also attenuated by intra-RVM administration of the nitric oxide synthase (NOS) inhibitor L-NAME. In support, there was a significant increase in the number of cells in the RVM labeled for NADPH diaphorase (NADPH-d) or neuronal NOS (nNOS) in zymosan-treated rats. In contrast to the effects of APV and L-NAME, administration of the non-NMDA receptor antagonist DNQX into the RVM further enhanced the already facilitated VMR to CRD in zymosan-treated rats. Taken together, these data suggest that zymosan-produced visceral hyperalgesia is influenced by two descending pain modulatory systems: a facilitatory system mediated by activation of NMDA receptors in the RVM and production of nitric oxide, and an inhibitory system mediated by activity at non-NMDA receptors in the RVM. The unmasking of one system by selective blockade of the other suggests simultaneous activation of both by colonic inflammation.
Coutinho
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VS
Department of Pharmacology, Bowen Science Building, University of Iowa College of Medicine, Iowa City, IA 52242, USA.
Urban
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OM
Gebhart
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FG
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D003106:Colon / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology*; D007150:Immunohistochemistry; D008297:Male; D008526:Medulla Oblongata / Q000201:enzymology / Q000503:physiopathology*; D008845:Microinjections; D009252:NADPH Dehydrogenase / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000502:physiology*; D014781:Viscera / Q000503:physiopathology*; D015054:Zymosan / Q000008:administration & dosage
D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D017470:Receptors, Glutamate; D009569:Nitric Oxide; C056723:FG 9041; D015763:2-Amino-5-phosphonovalerate; D015054:Zymosan; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D009252:NADPH Dehydrogenase; D019331:NG-Nitroarginine Methyl Ester