Abstract
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.
MeSH terms
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Amidines / administration & dosage
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Amidines / pharmacology*
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Analgesics / pharmacology*
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Animals
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Carrageenan
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Cerebellum / enzymology
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Heating
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Heterocyclic Compounds, 2-Ring / administration & dosage
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Heterocyclic Compounds, 2-Ring / pharmacology*
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Humans
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Hyperalgesia / chemically induced
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Hyperalgesia / drug therapy
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Hyperalgesia / enzymology
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Indazoles / pharmacology
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Injections, Intraperitoneal
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Injections, Spinal
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Male
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NG-Nitroarginine Methyl Ester / pharmacology
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Nitric Oxide Synthase / antagonists & inhibitors*
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Nitric Oxide Synthase Type I
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Nitric Oxide Synthase Type II
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Rats
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Rats, Wistar
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Recombinant Proteins / antagonists & inhibitors
Substances
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7-chloro-3-imino-5-methyl-2-azabicyclo(4.1.0)heptane
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Amidines
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Analgesics
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Heterocyclic Compounds, 2-Ring
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Indazoles
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Recombinant Proteins
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Carrageenan
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NOS1 protein, human
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NOS2 protein, human
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type I
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Nitric Oxide Synthase Type II
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Nos1 protein, rat
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Nos2 protein, rat
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7-nitroindazole
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NG-Nitroarginine Methyl Ester