The potent inducible nitric oxide synthase inhibitor ONO-1714 inhibits neuronal NOS and exerts antinociception in rats.
We evaluated if ONO-1714, known as an inducible nitric oxide synthase (iNOS) inhibitor, could inhibit neuronal NOS (nNOS) and exert antinociception. ONO-1714 potently inhibited both crude rat cerebellar NOS and recombinant human nNOS in vitro. Systemic ONO-1714 at 1-10 mg/kg suppressed carrageenan-induced thermal hyperalgesia in rats, an effect being equivalent to the antinociception caused by L-NAME or 7-nitroindazole at 25 mg/kg. The same doses of ONO-1714 also caused hypertension. Intrathecal (i.t.) ONO-1714 potently reduced the hyperalgesia, the effective dose range (0.2-0.6 microg/rat) being much lower than the antinociceptive dose (150 microg/rat) of i.t. L-NAME. Thus, ONO-1714 is considered a potent inhibitor of nNOS in addition to iNOS. The distinct relative antinociceptive activities of systemic and i.t. ONO-1714 are attributable to its possible poor blood-brain barrier permeability.
Sekiguchi
Fumiko
F
Division of Physiology and Pathophysiology, School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, 577-8502, Japan.
Mita
Yoko
Y
Kamanaka
Yoshihisa
Y
Kawao
Naoyuki
N
Matsuya
Hidekazu
H
Taga
Chiyomi
C
Kawabata
Atsufumi
A
D000578:Amidines / Q000008:administration & dosage / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002351:Carrageenan; D002531:Cerebellum / Q000201:enzymology; D006361:Heating; D006574:Heterocyclic Compounds, 2-Ring / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology; D007191:Indazoles / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
C407360:7-chloro-3-imino-5-methyl-2-azabicyclo(4.1.0)heptane; D000578:Amidines; D000700:Analgesics; D006574:Heterocyclic Compounds, 2-Ring; D007191:Indazoles; D011994:Recombinant Proteins; D002351:Carrageenan; C496320:NOS1 protein, human; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496322:Nos1 protein, rat; C496318:Nos2 protein, rat; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester