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REDOX MODULATION AT THE PERIPHERAL SITE ALTERS NOCICEPTIVE TRANSMISSION IN VIVO

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SUMMARY



The aim of the present study was to investigate the role of redox modulation during the peripheral nociceptive transmission in vivo. The nociceptive response was evaluated by the amount of time that mice spent licking the footpad injected with glutamate (20 µmol/paw). Thiol groups in footpad tissue were quantified using a colourimetric reaction with 5,5′-dithio-bis-2-nitrobenzoic acid (DTNB).



When coadministered with glutamate, the thiol alkylating agent iodoacetate (200 nmol/paw) caused significant antinociception in footpad tissue, in parallel with a decrease in free thiol groups. Treatment with the reducing agent dithiothreitol (200 nmol/paw) 5 min before glutamate and iodoacetate prevented the antinociception and thiol loss caused by iodoacetate. Injection of 100 nmol/paw ebselen (2-phenyl-1,2-benzisoselenazol-3[2H]-one), an in vitro redox modulator of the N-methyl-d-aspartate (NMDA) receptor, also prevented iodoacetate-induced antinociception. However, ebselen did not prevent thiol loss in the footpad. Dithiothreitol and ebselen had a synergic nociceptive effect with glutamate.



Alone, ebselen (100 nmol/paw) exhibited a pronociceptive effect. The nociception induced by ebselen was blocked by glutathione depletion induced by buthionine-sulphoximine (BSO; 2.5 µmol/paw). In addition, ebselen-induced nociception was prevented by 75 ± 2% following injection of 5 nmol/paw MK-801 (an NMDA receptor antagonist). The nitric oxide synthase inhibitor NG-nitro-l-arginine (250 nmol/paw) had no effect on the nociception produced by ebselen.



In conclusion, the present paper reports on the effect of redox modulation on the glutamatergic system during peripheral nociceptive transmission in vivo. Antinociception was directly correlated with the availability of thiol groups, whereas the pronociceptive response of the reducing agents likely occurs via positive modulation of the NMDA receptor.
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Keywords: ebselen; nociception; redox modulation; thiol groups

Document Type: Research Article

Publication date: March 1, 2009

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