Gabapentin Inhibits Bortezomib-Induced Mechanical Allodynia Through Supraspinal Action in Mice

Bortezomib, an inhibitor of proteasome holoenzyme, is used to treat relapsed and refractory multiple myeloma. Peripheral neuropathy is a treatment-limiting adverse effect of bortezomib and is very difficult to control. In this study, we examined the efficacy of gabapentin in inhibiting bortezomib-induced peripheral neuropathy. Single intravenous injections of bortezomib (0.03 – 0.3 mg/kg) dose-dependently induced mechanical allodynia with a peak effect 12 days after injection. Bortezomib (0.3 mg/kg) also caused mechanical hyperalgesia, but neither affected thermal nociception nor induced cold allodynia. Bortezomib increased the response of the saphenous nerve to weak punctate stimulation but not response to cool stimulation of the skin. When administered 12 days after bortezomib injection, oral and intracisternal gabapentin markedly inhibited mechanical allodynia. Intrathecal, but not intraplantar, gabapentin had a tendency to reduce mechanical allodynia. The antiallodynic activity of orally administered gabapentin was suppressed by noradrenaline, but not serotonin, depletion in the spinal cord. Bortezomib did not affect the expression levels of the calcium channel α2δ-1 subunit, a high-affinity binding site of gabapentin, in the plantar skin, spinal cord, medulla oblongata, and pons. These results suggest that gabapentin inhibits bortezomib-induced mechanical allodynia, most likely through the activation of the descending noradrenergic system. Keywords:: bortezomib, gabapentin, allodynia, descending noradrenergic system, noradrenaline