title: 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.
authors.affiliation: The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida 33136, USA. ahama@miami.edu
authors.forename: Aldric T
authors.initials: AT
authors.lastname: Hama
authors.forename: Alex
authors.initials: A
authors.lastname: Broadhead
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Lorrain
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Sagen
mesh_terms: D000700:Analgesics; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D002493:Central Nervous System Diseases / Q000188:drug therapy*; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000209:etiology; D009457:Neuroglia / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy*; D010812:Physical Stimulation; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000150:complications / Q000473:pathology; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects; D013117:Spinal Cord Compression / Q000150:complications / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D007212:Indolizines; D011720:Pyrazoles
chemical_list: D000700:Analgesics; D018927:Anti-Asthmatic Agents; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles