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.

The peptide Phα1β, from spider venom, acts as a TRPA1 channel antagonist with antinociceptive effects in mice

“…However, in vitro concentrations of Phα1β required to block TRPA1 channels are similar to those required to block VGCC (Vieira et al, ), suggesting that, in vivo, the actions of Phα1β could depend on VGCC inhibition. In agreement with a previous report (Kitamura et al, ), we failed to observe any protective effect by either i.pl. or i.t.…”

Strategies to Treat Chronic Pain and Strengthen Impaired Descending Noradrenergic Inhibitory System

“…Tanabe et al first reported the role of descending noradrenergic inhibition in gabapentin analgesia by demonstrating that depletion or blockade of noradrenergic signaling in the spinal cords of mice, after peripheral nerve injury, abolishes the antihypersensitivity effect of systemically administered gabapentin [25]. Similar behavioral results are also reported in various neuropathic pain rodent models, after systemic, intra-cerebroventricular, or intra-LC administration of gabapentin [26,27,28]. Gabapentin likely acts similarly in humans, because its oral administration at a dose that produces postoperative analgesia increases the noradrenaline concentration in the cerebrospinal fluid of patients with joint pain scheduled for orthopedic surgery [19].…”

“…Gabapentin, originally licensed as an antiepileptic drug in 1993, was rapidly recognized as an analgesic in patients and animals with neuropathic pain [25,26,27,28]. Gabapentin interacts with the α2δ subunit of voltage-gated calcium channels that modulates the release of excitatory amino acids in the spinal dorsal horn [29] and produces analgesia in transgenic mice with up-regulated α2δ-1 subunits, but not in normal mice [30], suggesting that the efficacy of gabapentin relies on the α2δ subunit.…”

“…Gabapentin often fails to provide sufficient analgesia in patients with neuropathic pain [1], in contrast to its remarkable and uniform efficacy in various neuropathic pain rodent models [25,26,28,44]. Although there are many different factors between humans and animals regarding neuropathic pain, the discrepancy between the clinical and preclinical efficacy of gabapentin may relate in part to the timing of studies in rodents, which are typically examined within 2–3 weeks after nerve injury.…”

Chemotherapy-induced peripheral neuropathy: part 1—current state of knowledge and perspectives for pharmacotherapy

“…Altered levels of several neurotransmitters, such as catecholamines, histamine, serotonin, glutamate and γ-aminobutyric acid (GABA), are associated with CIPN caused by vincristine [152,153], paclitaxel [154], oxaliplatin [155][156][157] and bortezomib [158].…”