The nitric oxide-cyclic GMP-protein kinase G-K+ channel pathway participates in the antiallodynic effect of spinal gabapentin.
The possible participation of the nitric oxide (NO)-cyclic GMP-protein kinase G (PKG) pathway on gabapentin-induced spinal antiallodynic activity was assessed in spinal nerve injured rats. Intrathecal gabapentin, diazoxide or pinacidil reduced tactile allodynia in a dose-dependent manner. Pretreatment with NG-L-nitro-arginine methyl ester (L-NAME, non-specific inhibitor of NO synthase NOS), 7-nitroindazole (neuronal NO synthase inhibitor), 1H-[1,2,4] -oxadiazolo [4,3-a] quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor) or (9S, 10R, 12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo-[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester (KT-5823, specific PKG inhibitor), but not NG-D-nitro-arginine methyl ester (D-NAME) or okadaic acid (protein phosphatase 1 and 2 inhibitor) prevented gabapentin-induced antiallodynia. Pinacidil activity was not blocked by L-NAME, D-NAME, 7-nitroindazole, ODQ, KT-5823 or okadaic acid. Moreover, KT-5823, glibenclamide (ATP-sensitive K+ channel blocker), apamin and charybdotoxin (small- and large-conductance Ca2+-activated K+ channel blockers, respectively), but not margatoxin (voltage-gated K+ channel blocker), L-NAME, 7-nitroindazole, ODQ or okadaic acid, reduced diazoxide-induced antiallodynia. Data suggest that gabapentin-induced spinal antiallodynia could be due to activation of the NO-cyclic GMP-PKG-K+ channel pathway.
Mixcoatl-Zecuatl
Teresa
T
Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados-Coapa, Calzada de los Tenorios 235, Colonia Granjas Coapa, 14330, México, DF, Mexico.
Flores-Murrieta
Francisco J
FJ
Granados-Soto
Vinicio
V
D000588:Amines / Q000008:administration & dosage / Q000494:pharmacology*; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D018999:Charybdotoxin / Q000494:pharmacology; D006152:Cyclic GMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D003981:Diazoxide / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D000077206:Gabapentin; D005905:Glyburide / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007278:Injections, Spinal; D019331:NG-Nitroarginine Methyl Ester / Q000737:chemistry / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control*; D020110:Pinacidil / Q000008:administration & dosage / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013127:Spinal Nerves / Q000293:injuries / Q000503:physiopathology; D013237:Stereoisomerism; D013997:Time Factors; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000494:pharmacology*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000588:Amines; D000700:Analgesics; D002227:Carbazoles; D003509:Cyclohexanecarboxylic Acids; D004791:Enzyme Inhibitors; D007191:Indazoles; D007211:Indoles; D010069:Oxadiazoles; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D047428:Protein Kinase Inhibitors; D011810:Quinoxalines; D014665:Vasodilator Agents; D018999:Charybdotoxin; C073601:KT 5823; D019319:Okadaic Acid; D001030:Apamin; D009569:Nitric Oxide; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D020110:Pinacidil; D019001:Nitric Oxide Synthase; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP; D003981:Diazoxide; D005905:Glyburide; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester