Anti-Hyperalgesic Effect of Isopulegol Involves GABA and NMDA Receptors in a Paclitaxel-Induced Neuropathic Pain Model.

Background: Neuropathic pain can be triggered by chemotherapy drugs such as paclitaxel (PTX). Management of pain is limited by drugs' ineffectiveness and adverse effects. Isopulegol (ISO) is a monoterpene present in the essential oils of several aromatic plants and has promising pharmacological activities. Objectives: to evaluate the antinociceptive activity of ISO in a PTX-induced neuropathic pain model. Methods: the toxicity of ISO was evaluated in healthy and cancerous cells. Behavioral assessments were performed using the von Frey and acetone tests. We investigated the involvement of the GABAergic pathway, NMDA, TNF-α, and the release of GABA and glutamate in the presence of ISO. Results: ISO showed little or no cytotoxicity in U87 and MDA-MB-231 cells. In both acute and subacute treatment, ISO at doses of 25, 50, and 100 mg/kg (* p < 0.05) increased the mechanical nociceptive threshold of neuropathic animals compared to the control group and reduced thermal sensitivity. Its action was reversed by pre-treatment with flumazenil and potentiated by the NMDA antagonist, MK-801. TNF-α and glutamate levels were reduced and GABA release was increased in the tests carried out. Conclusions: ISO shows low toxicity in neuronal cells and its association with PTX generated synergism in its cytotoxic action. The antinociceptive effect of ISO is due to activation of GABA and antagonism of NMDA receptors and involves the stabilization of neuronal plasma membranes leading to an imbalance in the release of neurotransmitters, favoring GABA-mediated inhibition over glutamatergic excitation.