Propentofylline reduces mechanical allodynia and induces mitogen-activated protein kinase phosphatase-1: An experimental study in a rat model of acute incisional pain

Abstract

ABSTRACTBackground: Acute postoperative pain can lead to long hospital stays, dysfunction, and even chronic pain. Mitogen-activated protein kinases (MAPKs) are important in pain signaling. The activity of MAPKs are negatively regulated by dual specificity phosphatases such as mitogen- activated protein kinase phosphatase-1 (MKP-1), which specifically dephosphorylates MAPK p38. Since, propentofylline (PPF) can reduce pain by inhibiting MAPKs, we hypothesized that PPF relieves acute pain by inducing MKP-1 levels.Objective: Investigating the anti-nociception effect of an intrathecal injection of PPF in a rat model of acute incisional pain and the role of MKP-1 and phospho-p38 in the mechanism by which PPF ameliorates acute pain.Methods: We assessed the mechanical withdrawal threshold (MWT) response before and after incisional pain surgery between a control group and a group receiving PPF, and also assessed the effect of pre-treatment with Ro 31–8220, an MKP-1 inhibitor, on PPF effects. Following the MWT, lumbar spinal cord samples were also analyzed by western blot analysis to determine MKP-1 and p-p38 levels.Results: Following surgery, the MWT response was decreased over 5 h–3 d accompanied by decreased expression of MKP-1 and increased p-p38 levels. An intrathecal injection of PPF increased the MWT response and increased spinal cord MKP-1 expression, but decreased p-p38 levels. Pre-treatment of rats with Ro31-8220 partly reversed the analgesic effect of PPF and its effect on MKP-1/p-p38 levels.Conclusions: This study suggests that an increase in MKP-1 levels and a corresponding decrease in p-p38 levels may be the mechanism by which PPF ameliorates acute pain.