Propentofylline Relieves Incisional Hyperalgesia by Regulating ERK1/2 Phosphorylation in Spinal Astrocytes and Microglia.

Spinal astrocytes, microglia and extracellular signal-regulated kinase 1 and 2 (ERK1/2) have been implicated in pain processing. This study investigated whether preoperative intrathecal propentofylline (PPF) attenuates acute incisional hyperalgesia in rats and whether the effect is associated with spinal glial markers and ERK1/2 phosphorylation. Sixty-six male Sprague-Dawley rats were randomly assigned to blank, incisional pain, normal saline, dimethyl sulphoxide, PPF and U0126 groups. Mechanical and thermal hyperalgesia were assessed at baseline and 2, 4, 8, 24 and 72 h after incision. Spinal neuronal and glial markers, p-ERK1/2 and inflammatory mediators were evaluated by Western blotting and immunofluorescence. Primary spinal astrocyte experiments were additionally used to examine ERK1/2-dependent inflammatory mediator release. Preoperative intrathecal PPF attenuated mechanical and thermal hyperalgesia throughout the 72-h observation period, whereas U0126 attenuated hyperalgesia mainly during the early post-incision period. At 4 h after incision, both treatments were associated with reduced spinal GFAP, Iba-1 and p-ERK1/2 expression and reduced TNF-α and COX-2 immunoreactivity. In cultured astrocytes, PPF reduced LPS-induced inflammatory mediator release, whereas constitutively active ERK1/2 attenuated this effect. These findings support an association between the antihyperalgesic effect of PPF and modulation of spinal glial, ERK1/2-related and inflammatory responses after incision.