Effect of diabetes on the mechanisms of intrathecal antinociception of sildenafil in rats.
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 microg) 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 microg), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor, 1-10 microg), 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 microg), but not N-D-nitro-arginine methyl ester (D-NAME, 50 microg) or saline, significantly diminished sildenafil (50 microg)-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.
Araiza-Saldaña
Claudia Ivonne
CI
Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados-Coapa, Calzada de los Tenorios 235, Colonia Granjas Coapa, 14330 México, D.F., Mexico.
Reyes-García
Gerardo
G
Bermúdez-Ocaña
Deysi Yadira
DY
Pérez-Severiano
Francisca
F
Granados-Soto
Vinicio
V
D000698:Analgesia / Q000379:methods; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005557:Formaldehyde; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D007211:Indoles / Q000494:pharmacology; D007278:Injections, Spinal; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010069:Oxadiazoles / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011687:Purines; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013311:Streptozocin / Q000008:administration & dosage / Q000633:toxicity; D013450:Sulfones; D013997:Time Factors
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D001786:Blood Glucose; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D010069:Oxadiazoles; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D026902:Potassium Channel Blockers; D011687:Purines; D011810:Quinoxalines; D013450:Sulfones; C073601:KT 5823; D005557:Formaldehyde; D013311:Streptozocin; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D019331:NG-Nitroarginine Methyl Ester