Controlling
neuropathic pain is an unmet medical need and we set out to identify new therapeutic candidates.
AV411 (
ibudilast) is a relatively nonselective
phosphodiesterase inhibitor that also suppresses glial-cell activation and can partition into the CNS. Recent data strongly implicate activated glial cells in the spinal cord in the development and maintenance of
neuropathic pain. We hypothesized that
AV411 might be effective in the treatment of
neuropathic pain and, hence, tested whether it attenuates the
mechanical allodynia induced in rats by chronic constriction injury (CCI) of the sciatic nerve, spinal nerve
ligation (SNL) and the chemotherapeutic
paclitaxel (
Taxol). Twice-daily systemic administration of
AV411 for multiple days resulted in a sustained attenuation of CCI-induced
allodynia. Reversal of
allodynia was of similar magnitude to that observed with
gabapentin and enhanced efficacy was observed in combination. We further show that multi-day
AV411 reduces SNL-induced
allodynia, and reverses and prevents
paclitaxel-induced
allodynia. Also,
AV411 cotreatment attenuates tolerance to
morphine in nerve-injured rats. Safety pharmacology, pharmacokinetic and initial mechanistic analyses were also performed. Overall, the results indicate that
AV411 is effective in diverse models of
neuropathic pain and support further exploration of its potential as a therapeutic agent for the treatment of
neuropathic pain.