Characterization of Fasudil in preclinical models of pain.

摘要

Activation of Rho kinase (ROCK) has been shown to play a role in neuronal regeneration and development of posttraumatic neuropathic pain. The ROCK inhibitor Fasudil, used clinically for the treatment of vasospasm, was used to investigate the analgesic profile of a ROCK inhibitor. Fasudil was evaluated in different preclinical models of neuropathic, osteoarthritic (OA), and inflammatory pain as well as capsaicin-induced acute pain and secondary mechanical hypersensitivity. In addition, Fasudil was tested in in vivo electrophysiology to determine the mechanism by which Fasudil produces analgesia. Fasudil at the highest dose tested (30 mg/kg) significantly attenuated mechanical allodynia in spinal-nerve ligation (SNL; 77%), chronic constriction injury (CCI; 53%), capsaicin-induced secondary mechanical hypersensitivity (63%), sodium iodoacetate-induced OA pain (88%), and capsaicin-induced acute flinching behaviors (56%). However, Fasudil (at 30 mg/kg) failed to attenuate or had only modest effects on inflammatory thermal hyperalgesia following carrageenan injection and mechanical allodynia following Complete Freund's Adjuvant (CFA) injection. Fasudil produced ED(50) of 10.8 mg/kg in the SNL, and 5.7 mg/kg in the OA pain models. The ED(50) and 95% CI could not be obtained in the other models. Furthermore, administration of Fasudil (10 mg/kg, iv) significantly reduced both spontaneous and evoked firing of wide dynamic range (WDR) neurons in SNL, but not sham rats. Finally, Fasudil significantly decreased exploratory behaviors at 30 mg/kg. These results suggest that the acute administration of a ROCK inhibitor produces efficacy in both neuropathic and nociceptive pain states at doses devoid of locomotor side effects, with specific effects on WDR neurons. PERSPECTIVE: In this article, the potential analgesic effects of Fasudil in a range of preclinical pain models were assessed. Fasudil was shown to have efficacy in neuropathic and nociceptive pain models. These findings may help identify new therapeutic treatments for pain in the clinic.