Effect of diabetes on the mechanisms of intrathecal antinociception of sildenafil in rats

Claudia Ivonne Araiza-Saldaña, Gerardo Reyes-García, Deysi Yadira Bermúdez-Ocaña, Francisca Pérez-Severiano, Vinicio Granados-Soto

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30 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)60-70
Number of pages11
JournalEuropean Journal of Pharmacology
Volume527
Issue number1-3
DOIs
StatePublished - 19 Dec 2005

Keywords

  • Cyclic GMP
  • K channel
  • Protein kinase G
  • Sildenafil
  • Spinal processing

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