A comparation of the antinociceptive effects of phosphodiesterase 5 inhibitors sildenafil and vardenafil on carrageenan-induced nociception in rats: Role of the nitric oxide-cGMP pathway and calcium

In this study, we aimed to compare the peripheral antinociception effects of specific phosphodiesterase 5 (PDE-5) inhibitors sildenafil and vardenafil on carrageenan-induced nociception in rats, and to investigate role of calcium besides the role of L-arginin/NO/cGMP pathway. Hyperalgesia was induced by the intraplantar injection of 0.1 mL fresh carrageenan solution to right hind-paw whereas, saline as a vehicle of carrageenan was injected to the left paw. This procedure was already described by Randall and Selitto (1957) as paw pressure test, and used for measuring mechanic nociception pressure via an analgesimeter. Pressure which produced nociception was measured before (0. minute) and after (15.,30., 60. and 120. minutes) carrageenan injection. Sildenafil (200 µg/i.pl) or vardenafil (50 or 100 µg/i.pl) injections which were 30 minutes prior to carrageenan, produced statistically significant antinociception effects by decreasing carrageenan-induced hyperalgesia compared to control group. Moreover, vardenafil-induced antinociception response in 100 µg/i.pl dose was more potent and early-initiated than 50 µg/i.pl vardenafil dose group. Comparison results between sildenafil and vardenafil groups showed that sildenafil produced more potent antinociception effect in 200 µg/i.pl dose than vardenafil-induced in 50 µg/i.pl dose whereas, results were similar in dose of 200 µg/i.pl sildenafil and 100 µg/i.pl vardenafil. Administration of L-arginin (NO donor-10 µg/i.pl) 10 minutes prior to sildenafil or vardenafil injections increased antinociception responses when L-NAME (NO synthase blocker-100 µg/i.pl) and ODQ (specific guanylate cyclase inhibitor-50 µg/i.pl) administrations produced a decrease in antinociception effect of sildenafil or vardenafil. Similarly, antinociception effects of sildenafil and vardenafil were also significantly attenuated in A23187 (Ca++ ionophore-1 µg/i.pl) injection. In conclusion, we demonstrated that sildenafil and vardenafil were significantly reduced carrageenan-induced peripheral nociception in rats and the inhibition of intracellular Ca++ entry besides the role of L-arginin/NO/cGMP pathway in this mechanism. In additon, in our study we firstly showed the peripheral antinociceptive effet of vardenafil and related-mechanism in rats.