The Antinociceptive Effect of the Asthma Drug Ibudilast in Rat Models of Peripheral and Central Neuropathic Pain

Abstract

Ibudilast, an asthma drug, has demonstrated antinociceptive effects in several rat models of peripheral neuropathic pain, and a proposed mechanism of action is the inhibition of release of the cytokine tumor necrosis factor-α (TNF-α) from activated spinal microglia. Spinal glial activation has also been demonstrated in rat models of central neuropathic pain following spinal cord injury (SCI). The current study evaluated the effect of a short course of treatment with ibudilast on SCI-induced pain, and for comparison, following a chronic constriction injury (CCI; the Bennett model) of the sciatic nerve in rats. The effects of ibudilast treatment on spinal (SCI and CCI rats), and nerve tissue (CCI only) TNF-α content were also evaluated. Following an acute midthoracic SCI with a microvascular clip (20-g force), hindpaw withdrawal thresholds were significantly decreased, indicating below-level cutaneous tactile hypersensitivity. Likewise, unilateral loose ligation of the sciatic nerve led to a robust ipsilateral tactile hypersensitivity. Rats were treated with either ibudilast (10 mg/kg IP) or vehicle (2 mL/kg) during the period of robust and steady hindpaw hypersensitivity for each model--CCI rats were treated 14-16 days post-surgery, and SCI rats were treated 30-32 days post-surgery--and tested daily. Ibudilast ameliorated hindpaw hypersensitivity in both SCI and CCI rats, whereas vehicle treatment had no effect. Interestingly, repeated treatment led to increased baseline thresholds, beyond the duration of the drug half-life, suggesting persistent changes in neuropathic pain processing. In SCI rats, an increase in TNF-α content in spinal tissue rostral to the SCI was observed. Ibudilast treatment did not significantly alter this increase. In rats with a CCI, TNF-α content was markedly increased in the ipsilateral sciatic nerve and was partially reduced following ibudilast, but not vehicle, treatment. Ibudilast could be useful for the treatment of neuropathic pain of central as well as peripheral origin.

Inhibition of Paclitaxel-induced Decreases in Calcium Signaling

“…In the past, lithium and ibudilast were tested as potential treatment options for the treatment of Taxol-induced peripheral neuropathy; however, neither compound was previously considered as a preventative measure against peripheral neuropathy (22,23,27,28). This study clearly shows that these candidate compounds are able to inhibit chemotherapy-induced changes in neuronal cells.…”

The Effects of the Toll-Like Receptor 4 Antagonist, Ibudilast, on Sevoflurane’s Minimum Alveolar Concentration and the Delayed Remifentanil-Induced Increase in the Minimum Alveolar Concentration in Rats

“…The ibudilast dose was selected based on its antinociceptive effects in rat models of peripheral and central neuropathic pain. 20,21 The remifentanil constant rate of infusion dose was selected based on its ability to produce opioid-induced hyperalgesia and tolerance in rats. 5 The naloxone dose was selected based on its ability to block opioid-induced hyperalgesia in rats.…”

“…16 Ibudilast may not only suppress the production of proinflammatory cytokines, such as tumor necrosis factor α and interleukin 1β, but also increase the production of the anti-inflammatory cytokine interleukin 10 and various neurotrophic factors. 14,[17][18][19][20] We hypothesized that ibudilast would significantly reduce the opioid tolerance effect associated with remifentanil in rats and, second, that it would have a significant MAC-sparing effect with sevoflurane.…”

Targeting Opioid-Induced Hyperalgesia in Clinical Treatment: Neurobiological Considerations

“…Accordingly, numerous groups are studying the potential of inhibiting the glial system to enhance treatment of pain. For instance, the glial inhibitor ibudilast (MN166) has shown promise in the treatment of allodynia in neuropathic pain in an animal model [215,216]. Considering that neuropathic pain and OIH share similar neurobiology, it is quite possible that targeting this system in treatment would reduce OIH and, in turn, increase the efficacy of opioid treatment.…”