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The antinociceptive effects of L-kynurenine in the writhing test may be mediated by interaction kynurenic acid-GPR35
, V. CARLÀ, G. MANNAIONI, D. MARATEA, F. MORONI;
Dept Pharmacol, Univ. Florence, Florence, Italy
Kynurenine is the primary degradation product of tryptophan and the origin of
the “kynurenine pathway”, a cascade of enzymatic steps that generate several
biologically active compounds, including kynurenic acid (KYNA) which has
both neuroprotective and antinociceptive properties. KYNA parenterally
administrated crosses the blood brain barrier poorly but s.c. administration of
100 mg/kg kynurenine can increase kynurenic acid in the blood and in the
brain (Chiarugi et al., J. Neurochem 67
, 692, 1996) this effect being potentited
by probenecid, an inhibitor of organic anion transport. GPR35, a formerly
“orphan receptor” activated by KYNA, is highly abundant in DRG and
possibly involved in nociception (Ohshiro et al., BBRC365
, 344, 2008). The
intraperitoneal injection of 0.6% acetic acid in mice induces the contraction of
the abdominal muscles together with stretching of the hind legs (“writhes”).
This so-called writhing test is used for antinociceptive screening and enables
We examined the effects of L-kynurenine (KYN) alone and in combination with probenecid on the writhing and monitored the levels of plasma KYNA from trunk blood after sacrifice at one hour following the drug treatments of mice. KYN (30, 100, 300 mg/kg s.c.) decreased the number of writhes by 16, 29 and 60% of controls, indicating an antinocicaptive/anti-inflamatory effect of the compound. KYN 100 mg/kg and 300 mg/kg dose-dependently increased plasma KYNA to 1068±190 pmol/ml and 2201±213 pmol/ml (controls: 49±10 pmol/ml), respectively, suggesting that the antinociceptive effect of KYN was due to the increased availability of KYNA. Co-administration of probenecid (200 mg/kg s.c) potentiated the antinociceptive effect of KYN (100 mg/kg) and increased plasma KYNA levels to 4610±712
pmol/ml. Probenecid by itself decreased the number of writhes and increased plasma KYNA to 268±87 pmol/ml. These results indicate that KYN has antinociceptive effects in the writhing test and suggest that KYNA mediated these effects.
, None; V. Carlà
, None; G. Mannaioni
, None; D. Maratea
None; F. Moroni
The work was in part supported by the IRPF
[Authors]. [Abstract Title]. Program No. XXX.XX. 2008 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2008. Online. 2008 Copyright by the Society for Neuroscience all rights reserved. Permission to republish any abstract or part of any abstract in any form must be obtained in writing by SfN office prior to publication.
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