Sildenafil induces hyperalgesia via activation of the NO-cGMP pathway in the rat neuropathic pain model

Abstract

Persistent stimulation of nociceptors and C-fibers by tissue injury causes hyperalgesia and allodynia by sensitization of nociceptors and facilitation of synaptic transmission in the spinal cord. The important participant in the inflammatory response of injured peripheral nerve may be nitric oxide (NO). The aim of the present study was to test the sensitivity of PDE5 inhibitor sildenafil in chronic constriction injury (CCI) model a rat model of neuropathic pain. Sciatic nerve injury is associated with development of hyperalgesia 14 days after the nerve ligation. Sildenafil (100 and 200 microg/rat, i.t.) produced a significant decrease in pain threshold, which in lower dose did not alter the nociceptive threshold. The hyperalgesic effect of sildenafil was blocked by L-NAME and methylene blue (MB), which on per se treatment showed antinociceptive effect in nerve ligated rats. The results from the present study indicated that the major activation of NO-cGMP pathway in the chronic constriction injury model of neuropathic pain. The aggravation of hyperalgesic response might be due to the increased cGMP levels resulting in PKG-I activation and its upregulation.

Evaluation of the protein biomarkers and the analgesic response to systemic methylene blue in patients with refractory neuropathic pain: a double-blind, controlled study

“… 31 Activation of NMDA receptors increases calcium conductance and activates the enzyme NOS, ultimately leading to NO synthesis and NO formation, which plays an important role in the development of allodynia. As MB is an inhibitor of soluble guanylate cyclase and NO, 17 , 18 administration of a NO antagonist may reduce allodynia, 32 and it may be considered responsible for these effects.…”

“… 16 In animal models, the administration of MB induced antinociceptive effects in sciatic nerve ligated models of neuropathic pain. 17 In chemically induced ischemia in rats, MB was demonstrated to play a dual role with a potent analgesic effect at lower doses, and a there was a dose-dependent reversal of the analgesic effect at higher doses. 18 Based on these animal studies, there appears to be the potential for the application of MB in the treatment of patients suffering from neuropathic pain conditions.…”

Sildenafilo oral en medicina neonatal “Investigado para adultos, usado también por neonatos”

“…Este efecto se pudo explicar por las concentraciones crecientes de GMPc central. Se ha demostrado que el sildenafilo induce hiperalgia por la activación de la vía del óxido nítrico-GMPc en el modelo neuropático de dolor de la rata 59 . En adultos, los informes recientes asocian el sildenafilo a un aumento de la reactividad cerebrovascular medida por Doppler transcraneal 60 , ataques agudos de cefaleas 61 , y el accidente cerebrovascular (stroke) 62 .…”

Effect of Sildenafil on Peripheral Nerve Regeneration

“…27 Single injection of sildenafil (100 and 200 Kg) produced a significant decrease in pain threshold in rats with nerve injury (nerve-ligated), suggesting that sildenafil activates the NO-cGMP pathway in the nerve damaged rats. 27 However, we did not observe this phenomenon in our study. The sildenafil itself will not induce the neuropathic pain, but decrease the pain threshold.…”

“…16,23,27 The cGMP has been given considerably less attention, although it mediates intracellular signaling cascades activated by extracellular guidance cues. The cGMP can promote neurite outgrowth in neuronal cell lines.…”