TY - JOUR
T1 - Effect of diabetes on the mechanisms of intrathecal antinociception of sildenafil in rats
AU - Araiza-Saldaña, Claudia Ivonne
AU - Reyes-García, Gerardo
AU - Bermúdez-Ocaña, Deysi Yadira
AU - Pérez-Severiano, Francisca
AU - Granados-Soto, Vinicio
PY - 2005/12/19
Y1 - 2005/12/19
N2 - The mechanism of intrathecal antinociceptive action of the phosphodiesterase 5 inhibitor sildenafil was assessed in diabetic rats using the formalin test. Intrathecal administration of sildenafil (12.5-50 μg) produced a dose-related antinociception during both phases of the formalin test in non-diabetic and diabetic rats. Intrathecal pretreatment with N-l-nitro-arginine methyl ester (l-NAME, nitric oxide (NO) synthase inhibitor, 1-50 μg), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor, 1-10 μg), KT5823 (protein kinase G (PKG) inhibitor, 5-500 ng), charybdotoxin (large-conductance Ca2+-activated K+ channel blocker, 0.01-1 ng), apamin (small-conductance Ca2+-activated K + channel blocker, 0.1-3 ng) and glibenclamide (ATP-sensitive K + channel blocker, 12.5-50 μg), but not N-d-nitro-arginine methyl ester (d-NAME, 50 μg) or saline, significantly diminished sildenafil (50 μg)-induced antinociception in non-diabetic rats. Intrathecal administration of ODQ, KT5823, apamin and glibenclamide, but not l-NAME nor charybdotoxin, reversed intrathecal antinociception induced by sildenafil in diabetic rats. Results suggest that sildenafil produces its intrathecal antinociceptive effect via activation of NO-cyclic GMP-PKG-K+ channels pathway in non-diabetic rats. Data suggest that diabetes leads to a dysfunction in NO and large-conductance Ca2+-activated K+ channels. Sildenafil could have a role in the pharmacotherapy of diabetes-associated pain.
AB - The mechanism of intrathecal antinociceptive action of the phosphodiesterase 5 inhibitor sildenafil was assessed in diabetic rats using the formalin test. Intrathecal administration of sildenafil (12.5-50 μg) produced a dose-related antinociception during both phases of the formalin test in non-diabetic and diabetic rats. Intrathecal pretreatment with N-l-nitro-arginine methyl ester (l-NAME, nitric oxide (NO) synthase inhibitor, 1-50 μg), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor, 1-10 μg), KT5823 (protein kinase G (PKG) inhibitor, 5-500 ng), charybdotoxin (large-conductance Ca2+-activated K+ channel blocker, 0.01-1 ng), apamin (small-conductance Ca2+-activated K + channel blocker, 0.1-3 ng) and glibenclamide (ATP-sensitive K + channel blocker, 12.5-50 μg), but not N-d-nitro-arginine methyl ester (d-NAME, 50 μg) or saline, significantly diminished sildenafil (50 μg)-induced antinociception in non-diabetic rats. Intrathecal administration of ODQ, KT5823, apamin and glibenclamide, but not l-NAME nor charybdotoxin, reversed intrathecal antinociception induced by sildenafil in diabetic rats. Results suggest that sildenafil produces its intrathecal antinociceptive effect via activation of NO-cyclic GMP-PKG-K+ channels pathway in non-diabetic rats. Data suggest that diabetes leads to a dysfunction in NO and large-conductance Ca2+-activated K+ channels. Sildenafil could have a role in the pharmacotherapy of diabetes-associated pain.
KW - Cyclic GMP
KW - K channel
KW - Protein kinase G
KW - Sildenafil
KW - Spinal processing
UR - http://www.scopus.com/inward/record.url?scp=28544437499&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2005.10.016
DO - 10.1016/j.ejphar.2005.10.016
M3 - Artículo
SN - 0014-2999
VL - 527
SP - 60
EP - 70
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-3
ER -