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

Abstract

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 3ʹ,5ʹ-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.

Neuropathic-like Nociception and Spinal Cord Neuroinflammation Are Dependent on the TRPA1 Channel in Multiple Sclerosis Models in Mice

“…Different findings, using the EAE mouse models, showedthat the upregulation of GFAP [16,52] correlates with MS physiopathology. The increase in GFAP expression was also related to pain-like behaviors in a model of neuropathic pain induced by spinal cord ligation [53][54][55]. Here, we reported that the deletion of TRPA1 prevents the increase in GFAP+ve cells observed in the wild-type mice induced in the two different MS mouse models.…”

Synergistic Antinociceptive Effects of Indomethacin–Pregabalin and Meloxicam–Pregabalin in Paclitaxel-Induced Neuropathic Pain

“…The analgesic effect of indomethacin, meloxicam, pregabalin, and their combinations on mechanical allodynia was also evaluated in the carrageenan-induced inflammatory pain model [ 35 , 36 ]. In brief, the baseline values of rats responding to mechanical stimuli were assessed before intraplantar injection of 20 μL of 2% carrageenan in the left hind paws.…”

Advancements in Phosphodiesterase 5 Inhibitors: Unveiling Present and Future Perspectives

“…Several animal studies have also proposed a beneficial pain-relieving effect of PDE5-Is in models of lesional [ 140 , 141 ] or metabolic neuropathic pain [ 142 ]. Sildenafil could ameliorate neuropathic pain symptoms in patients with diabetic peripheral neuropathy [ 143 ] and showed an antinociceptive effect in Sprague–Dawley male rats’ neuropathic pain models [ 144 ].…”