Abstract
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 ED50 of 10.8 mg/kg in the SNL, and 5.7 mg/kg in the OA pain models. The ED50 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.
Key words
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Article info
Publication history
Published online: March 25, 2010
Accepted:
December 29,
2009
Received in revised form:
December 9,
2009
Received:
August 31,
2009
Footnotes
Research support by Abbott Laboratories.
Identification
Copyright
© 2010 American Pain Society. Published by Elsevier Inc. All rights reserved.
