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.

Research on communication between glia and neurons has increased in the past decade. The onset of neuropathic pain, a major clinical problem that is not resolved by available therapeutics, involves activation of spinal cord glia through the release of proinflammatory cytokines in acute animal models of neuropathic pain. Here, we demonstrate for the first time that the spinal action of the proinflammatory cytokine, interleukin 1 (IL-1) is involved in maintaining persistent (2 months) allodynia induced by chronic-constriction injury (CCI). The anti-inflammatory cytokine IL-10 can suppress proinflammatory cytokines and spinal cord glial amplification of pain. Given that IL-1 is a key mediator of neuropathic pain, developing a clinically viable means of long-term delivery of IL-10 to the spinal cord is desirable. High doses of intrathecal IL-10-gene therapy using naked plasmid DNA (free pDNA-IL-10) is effective, but the dose required limits its potential clinical utility. Here we show that intrathecal gene therapy for neuropathic pain is improved sufficiently using two, distinct synthetic polymers, poly(lactic-co-glycolic) and polyethylenimine, that substantially lower doses of pDNA-IL-10 are effective. In conclusion, synthetic polymers used as i.t. gene-delivery systems are well-tolerated and improve the long-duration efficacy of pDNA-IL-10 gene therapy.

This commentary on coderre & katz, wiesenfeld-hallin et al., and dickenson focuses on: (a) the brain as an under-recognized contributor to pain facilitation at the spinal cord; (b) these brain-to-spinal pathways being activated by learning or by body infection/inflammation; and (c) the resultant spinal release of anti-analgesic neuropeptides, activators of the NMDA-NO cascade, and activators of glia.

A domiciliary survey (sample size circa 6000) was conducted in areas of different aircraft noise exposure affected by London (Heathrow) Airport. Respondents were urban dwellers aged 16+. Their use of medicines, general practitioner services, hospital facilities and community services were investigated in relation both to the level of aircraft noise and to the degree of annoyance it causes. None of the indicators showed higher uptake in the high noise areas. The relationships between health indicators, noise and annoyance were not uniform. In areas exposed to high noise the use of non-prescribed drugs was significantly higher among ‘very annoyed’ than among ‘less annoyed’ respondents. The uptake of psychotropic drugs, and the use of general practice and out-patient services, tended to increase with increasing annoyance both in high- and low-noise areas, but the differences were not in all cases statistically significant. Parallels were drawn between these results and those of earlier analyses of the same survey related to the prevalence of acute and chronic symptoms. Suggestions for the analysis and interpretation of health effects of noise are put forward.