Losmapimod, an Oral Anti-p38 MAP Kinase, Demonstrates Anti-Neuropathic and Anti-Inflammatory Effects in Rat Acute...

Background: The postoperative period is a large provider of acute and chronic pain which often combine pronociceptive, neuropathic and inflammatory components. As p38 MAPkinases are involved in pain response, this study aimed to evaluate the effect of losmapimod, an oral p38 MAPkinase inhibitor at the very first stage of acute neuropathic pain. Losmapimod efficacy was also compared with other well-known pain-relieving drugs and its dose response determined after inflammatory pain. Methods: The anti-neuropathic properties of losmapimod were evaluated after acute neuropathic pain (from day 0 to day 3 after sciatic nerve ligation) using thermal and mechanical stimulation. Losmapimod was also compared with gabapentin, their respective ED₅₀ were determined, and their interaction was studied using an isobolographic approach. The anti-inflammatory characteristics of losmapimod were assessed from day 0 to day 5 after carrageenan injection in the rat hind paw and compared with those of ketoprofen, ketamine, and morphine using paw oedema volume. Results: Losmapimod provided a potent analgesic effect after acute neuropathic pain. The ED₅₀ with their 95% confidence intervals of losmapimod and gabapentin were 10.5 (6.9-12.9) mg/kg and 18.2 (15.0-20.3) mg/kg, respectively. Their interaction was additive. Losmapimod also had a potent anti-inflammatory effect (ED₅₀ was 34 (19.0-246) mg/kg) with significant reduction of paw oedema (similarly to ketoprofen). Conclusions: Losmapimod showed anti neuropathic properties at the very early stage of neuropathic pain and potent anti-inflammatory properties. As previous studies have highlighted the excellent tolerance of losmapimod in human populations, this drug seems promising for acute postoperative pain, which combines both acute neuropathic and inflammatory mechanisms.