Expression of nitric oxide synthase isoforms in the dorsal horn of monoarthritic rats: effects of competitive and uncompetitive <Emphasis Type="Italic">N</Emphasis>-methyl-D-aspartate antagonists |
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Authors: | Claudio Infante Marcelo Díaz Alejandro Hernández Luis Constandil Teresa Pelissier |
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Institution: | (1) Program of Physiopathology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Ave. Salvador 486, P.O. Box 16038, Santiago 9, Santiago, Chile;(2) Laboratory of Neurobiology, Department of Biology, Faculty of Chemistry and Biology, University of Santiago of Chile (USACH), Ave. B. Libertador B. O'Higgins 3363, P.O. Box 40, Correo 33, Santiago, Chile;(3) Program of Molecular and Clinical Pharmacology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Independencia 1027, P.O. Box 70000, Santiago 7, Santiago, Chile |
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Abstract: | Chronic pain is associated with N-methyl-D-aspartate (NMDA) receptor activation and downstream production of nitric oxide, which has a pivotal role in multisynaptic
local circuit nociceptive processing in the spinal cord. The formation of nitric oxide is catalyzed by three major nitric
oxide synthase (NOS) isoforms (neuronal, nNOS; inducible, iNOS; endothelial, eNOS), which are increased in the spinal cord
of rodents subjected to some tonic and chronic forms of experimental pain. Despite the important role of NOS in spinal cord
nociceptive transmission, there have been no studies exploring the effect of NMDA receptor blockade on NOS expression in the
dorsal horn during chronic pain. Furthermore, NOS isoforms have not been fully characterized in the dorsal horn of animals
subjected to arthritic pain. The aim of this work was therefore to study the expression of nNOS, iNOS and eNOS in the dorsal
horns of monoarthritic rats, and the modifications in NOS expression induced by pharmacological blockade of spinal cord NMDA
receptors. Monoarthritis was produced by intra-articular injection of complete Freund's adjuvant into the right tibio-tarsal
joint. At week 4, monoarthritic rats were given either the competitive NMDA antagonist (±)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic
acid (CPP) or the uncompetitive NMDA antagonist ketamine. After 6 and 24 hours, animals were killed and posterior quadrants
of the lumbar spinal cord were dissected. Sample tissues were homogenized and subjected to immunoblotting with anti-nNOS,
anti-iNOS or anti-eNOS monoclonal antibodies. The nNOS isoform, but not the iNOS and eNOS isoforms, were detected in the dorsal
horns of control rats. Monoarthritis increased the expression of nNOS, iNOS and eNOS in the dorsal horns ipsilateral and contralateral
to the inflamed hindpaw. Intrathecal administration of CPP and ketamine reduced nNOS expression in monoarthritic rats but
increased the expression of iNOS and eNOS. Results suggest that blockade of spinal cord NMDA receptors produces complex regulatory
changes in the expression of NOS isoforms in monoarthritic rats that may be relevant for nitridergic neuronal/glial mechanisms
involved in the pathophysiology of monoarthritis and in the pharmacological response to drugs interacting with NMDA receptors. |
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