Spinal cord heme oxygenase participates in glutamate-induced pain-related behaviors.
Heme oxygenase catalyzes the formation of CO, Fe(2+) and biliverdin from the substrate heme. In these studies, we attempted to define the roles heme oxygenase play in pain-related behaviors induced by intrathecal injection of the spinal neurotransmitter glutamate. The intrathecal injection of glutamate or the more selective agonists N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) in C57Bl/6 mice lead to caudally directed pain behaviors which were sensitive to the heme oxygenase inhibitors tin protoporphyrin (Sn-protoporphyrin) and chromium mesoporphyrin (Cr-mesoporphyrin). Intrathecal injections of glutamate in heme oxygenase type 2 (HO-2) null-mutant animals resulted in reduced pain-related behaviors when compared with wild type animals. Glutamate, NMDA and AMPA stimulated cGMP accumulation in mouse spinal cord slices, which was blocked by heme oxygenase inhibitors. Glutamate did not stimulate cGMP production in HO-2 null-mutant animals. Our data are consistent with the hypothesis that pain-related behaviors induced by spinal glutamate rely on the activation of HO-2 and subsequent production of cGMP.
Li
Xiangqi
X
Veterans Affairs Palo Alto Health Care System and Stanford University Department of Anesthesiology, 112A, 3801 Miranda Ave., Palo Alto, CA 94304, USA.
Clark
J David
JD
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D006152:Cyclic GMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D066298:In Vitro Techniques; D007278:Injections, Spinal; D008297:Male; D008652:Mesoporphyrins / Q000494:pharmacology; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000494:pharmacology; D010146:Pain / Q000378:metabolism / Q000523:psychology*; D011524:Protoporphyrins / Q000494:pharmacology; D013116:Spinal Cord / Q000201:enzymology* / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D018690:Excitatory Amino Acid Agonists; D008652:Mesoporphyrins; D008665:Metalloporphyrins; D011524:Protoporphyrins; C427471:chromium mesoporphyrin; D018698:Glutamic Acid; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C032628:tin protoporphyrin IX; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2; D006152:Cyclic GMP