TY - JOUR
T1 - Activation and up-regulation of spinal cord nitric oxide receptor, soluble guanylate cyclase, after formalin injection into the rat hind paw
AU - Tao, Y. X.
AU - Johns, R. A.
N1 - Funding Information:
This work is supported by NIH Grants RO1 GM49111 and RO1 HL39706. The authors thank Mrs. Claire F. Levine for her assistance in western blot analysis and Mrs. Fengying Wang for her help in Fos immunohistochemistry.
PY - 2002/6/18
Y1 - 2002/6/18
N2 - 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 α1 subunit but not the β1 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 α1 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 α1 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.
AB - 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 α1 subunit but not the β1 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 α1 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 α1 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.
KW - Expression
KW - Inflammation
KW - Long-term hyperalgesia
KW - N-methyl-D-aspartate receptor
KW - Pain
KW - c-fos
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U2 - 10.1016/S0306-4522(02)00075-1
DO - 10.1016/S0306-4522(02)00075-1
M3 - Article
C2 - 12044461
AN - SCOPUS:0037129921
SN - 0306-4522
VL - 112
SP - 439
EP - 446
JO - Neuroscience
JF - Neuroscience
IS - 2
ER -