title: Activation and up-regulation of spinal cord nitric oxide receptor, soluble guanylate cyclase, after formalin injection into the rat hind paw.
abstract: Nitric oxide synthase is expressed abundantly in the spinal cord, and nitric oxide (NO) has been shown to play important roles in the central mechanism of inflammatory hyperalgesia. However, the expression and function of the NO receptor, soluble guanylate cyclase, is not fully understood in this processing at the spinal cord level. In the present study, we report that the soluble guanylate cyclase alpha(1) subunit but not the beta(1) subunit was expressed in rat spinal cord, particularly in the dorsal horn. We showed that intrathecal administration of a selective inhibitor of soluble guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, produced a significant anti-nociception demonstrated by the decrease in the number of flinches and shakes in the formalin-induced inflammatory pain model. This was accompanied by a marked reduction in formalin-induced c-fos expression in the spinal cord. During formalin-induced long-lasting inflammation, we found that the expression of the alpha(1) subunit of soluble guanylate cyclase was dramatically increased in the lumbar spinal cord on the second and fourth days after formalin injection into the dorsal side of a hind paw. Intraperitoneal pretreatment with an N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine maleate (MK-801), and a neuronal NO synthase inhibitor, 7-nitroindazole, not only significantly blocked formalin-induced secondary thermal hyperalgesia but also suppressed formalin-produced increase in the alpha(1) subunit of soluble guanylate cyclase in the spinal cord. The present results indicate that peripheral inflammation not only initially activates but also later up-regulates soluble guanylate cyclase expression via the NMDA receptor-NO signaling pathway, suggesting that soluble guanylate cyclase might be involved in the central mechanism of formalin-induced inflammatory hyperalgesia in the spinal cord.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Blalock 1415, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287-4965, USA.
authors.forename: Y-X
authors.initials: YX
authors.lastname: Tao
authors.forename: R A
authors.initials: RA
authors.lastname: Johns
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D005557:Formaldehyde; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006614:Hindlimb / Q000187:drug effects; D006930:Hyperalgesia / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052248:Nitric Oxide Synthase Type I; D010069:Oxadiazoles / Q000008:administration & dosage; D010147:Pain Measurement / Q000187:drug effects; D021122:Protein Subunits; D011810:Quinoxalines / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D000071756:Soluble Guanylyl Cyclase; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D014018:Tissue Distribution; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D010069:Oxadiazoles; D021122:Protein Subunits; D011810:Quinoxalines; D018160:Receptors, Cytoplasmic and Nuclear; D016194:Receptors, N-Methyl-D-Aspartate; D005557:Formaldehyde; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase