Antinociceptive Effect of Lodenafil Carbonate in Rodent Models of Inflammatory Pain and Spinal Nerve Ligation-Induced Neuropathic Pain.

Introduction New therapeutic alternatives for pain relief include the use of phosphodiesterase-5 (PDE5) inhibitors, which could prevent the transmission of painful stimuli by neuron hyperpolarization via nitric oxide (NO)/cyclic 3',5'-guanosine monophosphate (cGMP) pathway. The present work investigated the antinociceptive activity of a new PDE5 inhibitor, lodenafil carbonate, in inflammatory and neuropathic pain models. Methods and Results Although no effect was detected on neurogenic phase of formalin test in mice, oral administration of lodenafil carbonate dose-dependently reduced reactivity in the inflammatory phase (200.6 ± 39.1 to 81.9 ± 18.8 s at 10 μmol/kg, p= 0.0172) and this effect was totally blocked by NO synthase inhibitor, L-Nω-nitroarginine methyl ester (L-NAME). Lodenafil carbonate (10 μmol/kg p.o.) significantly reduced nociceptive response as demonstrated by increased paw withdrawal latency to thermal stimulus (from 6.8 ± 0.7 to 10.6 ± 1.3 s, p= 0.0006) and paw withdrawal threshold to compressive force (from 188.0 ± 14.0 to 252.5 ± 5.3 g, p<0.0001) in carrageenan-induced paw inflammation model. In a spinal nerve ligation-induced neuropathic pain, oral lodenafil carbonate (10 μmol/kg) also reversed thermal hyperalgesia and mechanical allodynia by increasing paw withdrawal latency from 17.9 ± 1.5 to 22.8 ± 1.9 s (p= 0.0062) and paw withdrawal threshold from 26.0 ± 2.8 to 41.4 ± 2.9 g (p= 0.0196). These effects were reinforced by the reduced GFAP (3.4 ± 0.5 to 1.4 ± 0.3%, p= 0.0253) and TNF-alpha (1.1 ± 0.1 to 0.4 ± 0.1%, p= 0.0111) stained area densities as detected by immunofluorescence in ipsilateral dorsal horns. Conclusion Lodenafil carbonate demonstrates important analgesic activity by promoting presynaptic hyperpolarization and preventing neuroplastic changes, which may perpetuate chronic pain, thus representing a potential treatment for neuropathic pain.