Preventative and therapeutic effects of a GABA transporter 1 inhibitor administered systemically in a mouse model of paclitaxel-induced neuropathic pain

Abstract

BackgroundThere is a dearth of drugs to manage a dose-limiting painful peripheral neuropathy induced by paclitaxel in some patients during the treatment of cancer. Gamma-aminobutyric acid transporter-1 (GAT-1) whose expression is increased in the brain and spinal cord during paclitaxel-induced neuropathic pain (PINP) might be a potential therapeutic target for managing PINP. Thus, our aim was to evaluate if systemic administration of a GAT-1 inhibitor ameliorates PINP.MethodsThe reaction latency to thermal stimuli (hot plate test; at 55 °C) and cold stimuli (cold plate test; at 4 °C) of female BALB/c mice was recorded before and after intraperitoneal treatment with paclitaxel, its vehicle, and/or a selective GAT-1 inhibitor NO-711. The effects of NO-711 on motor coordination were evaluated using the rotarod test at a constant speed of 4 rpm or accelerating mode from 4 rpm to 40 rpm over 5 min.ResultsThe coadministration of paclitaxel with NO-711 3 mg/kg prevented the development of paclitaxel-induced thermal hyperalgesia and cold allodynia at day 7 after drug treatment. NO-711 at 3 mg/kg produced antihyperalgesic activity up to 1 h and antiallodynic activity up to 2 h in mice with established paclitaxel-induced thermal hyperalgesia and cold allodynia. No motor deficits were observed with NO-711 at a dose of 3 mg/kg, whereas a higher dose 5 mg/kg caused motor impairment and reduced mean time spent on the rotarod at a constant speed of 4 rpm. However, at a rotarod accelerating mode from 4 rpm to 40 rpm over 5 min, NO-711 3 mg/kg caused motor impairment up to 1 h, but had recovered by 2 h.ConclusionsThese results show that systemic administration of the GAT-1 inhibitor NO-711 has preventative and therapeutic activity against paclitaxel-induced thermal hyperalgesia and cold allodynia. NO-711’s antiallodynic effects, but not antihyperalgesic effects, were independent of its motor impairment/sedation properties. Thus, low doses of GAT-1 inhibitors could be useful for the prevention and treatment of PINP with proper dose titration to reduce motor impairment/sedation side effects.

β-Caryophyllene, a CB2-Receptor-Selective Phytocannabinoid, Suppresses Mechanical Allodynia in a Mouse Model of Antiretroviral-Induced Neuropathic Pain

“…Thermal sensitivity was assessed using the hot or cold plate (Panlab SL, Barcelona, Spain) at 55 ± 1 • C or 4 ± 1 • C, as described before [12,92,93]. Briefly, each mouse was placed individually in a hot or cold plate, and the first sign of nociception, paw licking, flinching or jump response to avoid the heat or cold was recorded and the animal immediately removed from the plate.…”

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

“…Decreased GABAergic neurotransmission due to excessive IL-17 levels in the spinal cord has been linked to CIPN caused by paclitaxel [171], and the inhibition of GABA reuptake with by NO-711, a selective GABA transporter isoform 1 (GAT-1) inhibitor [172], prevents the development of thermal hyperalgesia and allodynia in paclitaxel-treated mice. NO-711 is also therapeutically effective for pre-existing CIPN [173]. Also, GABAergic precursor cell transplants reverse paclitaxel-induced mechanical hypersensitivity [174].…”

Acupuncture for Paclitaxel-Induced Peripheral Neuropathy: A Review of Clinical and Basic Studies

“… 64 During PIPN in rodents, dysregulation of the γ-aminobutyric acid (GABA) neurotransmitter system, which is involved in the pathogenesis of neuropathic pain, was confirmed in the ACC via observing a significant increase in gene expression of GABA transporter-1 (GAT-1). 62 , 63 GAT-1 is the major transporter responsible for GABA uptake from the synapses in the brain. It has been confirmed that blockage of GAT-1 ameliorated PIPN, indicating a significant role of GAT-1 in the pathophysiology of PIPN.…”