Diosmetina atenua a nocicepção em modelos de dor neuropática e musculoesquelética induzida pelos antineoplásicos paclitaxel e anastrozol em camundongos

Abstract

Cancer patients undergoing treatment often develop painful symptoms, which may be caused by the tumor itself, surgical procedures, or adverse effects of antineoplastic treatment. Two drugs used in the treatment of breast cancer, paclitaxel and anastrozole, frequently induce painful symptoms during and after treatment. Paclitaxel is a chemotherapeutic agent that causes acute and chronic neuropathic pain, while antineoplastic anastrozole commonly induces musculoskeletal pain syndromes in patients. Currently available treatments for relieving pain symptoms caused by antineoplastic agents have limited efficacy and produce adverse effects that restrict their use. Thus, diosmetin, a naturally occurring flavonoid, has shown promising results in the treatment of pathological conditions in preclinical models. Therefore, we investigated whether diosmetin presents itself as a formidable candidate for reducing antinociceptive effects in models of neuropathic pain induced by paclitaxel and musculoskeletal pain caused by anastrozole.. The model of neuropathic pain caused by paclitaxel was induced by single or repeated administrations of paclitaxel (1 mg/kg, intraperitoneal, i.p.) in male C57BL/6 mice (CEUA approval no. 4400060223), assessing parameters of mechanical and cold allodynia, as well as affective-motivational pain behavior. The model of musculoskeletal pain induced by anastrozole was established through an oral administration of anastrozole (0.2 mg/kg, p.o.), evaluating mechanical allodynia, affective-motivational pain behavior, and muscle strength. Paclitaxel induced pain-related parameters in both acute and chronic protocols, while anastrozole induced transient musculoskeletal pain symptoms. Different doses of diosmetin (0.015, 0.15, and 1.5 mg/kg, oral, p.o.) reversed paclitaxel-induced pain parameters, so the selected dose (0.15 mg/kg) for subsequent tests also reversed nociceptive parameters caused by anastrozole. The combination of both antineoplastic agents exacerbated mechanical allodynia compared to each drug alone, which was also reversed by diosmetin. Thus, diosmetin emerges as a potential therapeutic alternative for the treatment of pain conditions induced by antineoplastic agents such as paclitaxel and anastrozole