NEURONAL NITRIC OXIDE SYNTHASE, PKG AND ATP-SENSITIVE  K⁺ CHANNELS ARE INVOLVED IN THE ANTINOCICEPTION INDUCED BY Crotalus durissus terrificus VENOM (CdtV)

PICOLO, G.(1), CASSOLA, A.C. (2), CURY, Y. (1)

(1)Laboratório de Fisiopatologia, Instituto Butantan, (2)Instituto de Ciências Biomédicas, USP, Brasil.

The CdtV exerts peripheral antinociceptive effect in the carragenin (CG) and PGE₂-induced hyperalgesia, mediated by  d- (Eur. J. Pharmacol. 391:55-62, 2000) and k and d- peripheral opioid receptors, respectively, and by L-arginine-NO-cGMP pathway stimulation. Here we investigated the isoform of nitric oxide synthase(NOS) responsible for NO production and the participation of PKG and K⁺ channels in this effect. The rat paw pressure test, using CG or PGE₂ as nociceptive stimulus, was used to evaluate pain threshold. The test was applied before and 3 h after the i.pl. injection of CG (200 µg/paw) or PGE₂ (100 ng/paw). The antinociception induced by CdtV (200 µg/kg, p.o.) was blocked by 7-NI (50 µg/paw), but was not altered by L-NIL (50 µg/paw), neuronal and inducible NOS inhibitors, respectively. Rp-cGMP triethylamine (1.5 or 3 µg/paw), a PKG inhibitor, was able to partially reverse venom effect. TEA (640 µg/paw) or 4- AP (100 µg/paw) and charybdotoxin (2 µg/paw) or apamin(10 µg/paw), blockers of voltage-dependent and Ca⁺²-sensitive K⁺ channels, respectively, did not modify the antinociception. Glybenclamide (80 µg/paw), a blocker of ATP-sensitive K⁺ channels, blocked the venom effect. These data suggest that: a) neuronal nitric oxide cause analgesia, independently of the type of opioid receptor stimulated  (k or d), b) the effect of CdtV involves the generation of neuronal NO, the stimulation of PKG and the opening of ATP-sensitive K⁺ channels.

Financial support:FAPESP, CNPq.

CORRESPONDENCE TO:

PICOLO, G., Laboratório de Fisiopatologia, Instituto Butantan, Avenida Vital Brazil, 1500, 05503-900, São Paulo, SP, Brasil, Email gipicolo@usp.br