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

Marcio Carneiro Vieira; Fernanda Bezerra de Mello Monte; Bruno Eduardo Dematte; Tadeu Lima Montagnoli; Guilherme Carneiro Montes; Jaqueline Soares da Silva; Rosalia Mendez-Otero; Margarete Manhães Trachez; Roberto Takashi Sudo; Gisele Zapata-Sudo

doi:10.2147/JPR.S295265

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

J Pain Res. 2021 Mar 30:14:857-866. doi: 10.2147/JPR.S295265. eCollection 2021.

Affiliations

¹ Programa de Pós-graduação em Ciências Cirúrgicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, Brazil.
² Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, Brazil.
³ Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902, Brazil.
⁴ Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio De Janeiro, 21941-902, Brazil.

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 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.

Keywords: GFAP; inflammatory pain; lodenafil carbonate; neuropathic pain; phosphodiesterase 5 inhibitor; spinal cord.