title: Gabapentin inhibits bortezomib-induced mechanical allodynia through supraspinal action in mice.
abstract: 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.
authors.affiliation: Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Kitamura
authors.forename: Tsugunobu
authors.initials: T
authors.lastname: Andoh
authors.forename: Shizuka
authors.initials: S
authors.lastname: Mizoguchi
authors.forename: Yukako
authors.initials: Y
authors.lastname: Saito
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takahata
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kuraishi
mesh_terms: D059331:Adrenergic Neurons / Q000502:physiology; D000588:Amines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000037:antagonists & inhibitors*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects* / Q000037:antagonists & inhibitors*; D000069286:Bortezomib; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000077206:Gabapentin; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009638:Norepinephrine / Q000502:physiology; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000037:antagonists & inhibitors*; D013116:Spinal Cord / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000588:Amines; D000970:Antineoplastic Agents; D001897:Boronic Acids; D003509:Cyclohexanecarboxylic Acids; D011719:Pyrazines; D005680:gamma-Aminobutyric Acid; D000069286:Bortezomib; D000077206:Gabapentin; D009638:Norepinephrine