Effect of sildenafil on neuropathic pain and hemodynamics in rats

Abstract

Purpose: The inhibition of phosphodiesterase 5 produces an antinociception through the increase of cyclic guanosine monophosphate (cGMP), and increasing cGMP levels enhance the release of gamma-aminobutyric acid (GABA). Furthermore, this phosphodiesterase 5 plays a pivotal role in the regulation of the vasodilatation associated to cGMP. In this work, we examined the contribution of GABA receptors to the effect of sildenafil, a phosphodiesterase 5 inhibitor, in a neuropathic pain rat, and assessed the hemodynamic effect of sildenafil in normal rats.

Materials and methods: Neuropathic pain was induced by ligation of L5/6 spinal nerves in Sprague-Dawley male rats. After observing the effect of intravenous sildenafil on neuropathic pain, GABAA receptor antagonist (bicuculline) and GABAB receptor antagonist (saclofen) were administered prior to delivery of sildenafil to determine the role of GABA receptors in the activity of sildenafil. For hemodynamic measurements, catheters were inserted into the tail artery. Mean arterial pressure (MAP) and heart rate (HR) were measured over 60 min following administration of sildenafil.

Results: Intravenous sildenafil dose-dependently increased the withdrawal threshold to the von Frey filament application in the ligated paw. Intravenous bicuculline and saclofen reversed the antinociception of sildenafil. Intravenous sildenafil increased the magnitude of MAP reduction at the maximal dosage, but it did not affect HR response.

Conclusion: These results suggest that sildenafil is active in causing neuropathic pain. Both GABAA and GABAB receptors are involved in the antinociceptive effect of sildenafil. Additionally, intravenous sildenafil reduces MAP without affecting HR.

Keywords: Antinociception; GABA receptor; Sprague-Dawley rat; hemodynamics; neuropathic pain; sildenafil.

Fig. 1

Temporal effect and dose response curves of intravenous saline (control) and sildenafil (n = 37) on mechanical threshold in rats following ligation of L_5/6 spinal nerves. Data are presented as paw withdrawal threshold (A) and %MPE (B). Intravenous sildenafil increased the withdrawal threshold in a dose-dependent manner. Each line or bar represents mean ± SEM. BL, baseline. Compared with control, ^*p< 0.05, ^†p< 0.01.

Fig. 2

The effects of intravenous bicuculline (16 mg/kg, n = 7) and saclofen (16 mg/kg, n = 8) on the antinociception by intravenous sildenafil (30 mg/kg) in spinal nerve ligation-induced neuropathic pain. Bicuculline and saclofen were administered 10 min before the delivery of sildenafil. Data are presented as %MPE. Both bicuculline and saclofen attenuated the antinociception of sildenafil. Neither bicuculline (n = 5) nor saclofen (n = 6) alone affected the control response. Each bar represents mean ± SEM. Compared with sildenafil, ^*p< 0.05, ^†p< 0.01.

Fig. 3

Temporal effect of intravenous saline and sildenafil (n = 25) on mean arterial pressure (MAP, A) and heart rate (HR, B). Saline (control) and sildenafil were administered at time 0. Percent change of MAP and HR from baseline is plotted against time. Each line represents mean ± SEM. Compared with baseline, ^*p< 0.05.