The Involvement of Central Noradrenergic Pathway in the Analgesic Effect of Bee Venom Acupuncture on Vincristine-Induced Peripheral Neuropathy in Rats.

Daxian Li,Geehoon Chung,Sun Kwang Kim

doi:10.3390/toxins12120775

Abstract

Vincristine is a vinca alkaloid anti-mitotic drug with a broad spectrum of effects on solid and hematologic cancers. The major dose-limiting factor of this anti-cancer regimen is painful peripheral neuropathy. However, no gold-standard analgesic option has been used clinically. In this study, we investigated the effects and mechanism of bee venom acupuncture (BVA) to alleviate peripheral neuropathic pain induced by repeated intraperitoneal infusions of vincristine (1 mg/kg/day, days 1–5 and 8–12) in rats. Subcutaneous injection with bee venom (BV, 1.0 mg/kg) at the ST36 acupoint ameliorated cold and mechanical hypersensitivity (i.e., aberrant withdrawal responses in acetone drop and von Frey hair tests, respectively). In vivo extracellular recording demonstrated that BVA inhibited cutaneous cold (acetone) and mechanical (brush, press, and pinch) stimuli-elicited abnormal hyperexcitation of the spinal wide dynamic range (WDR) neurons in vincristine-treated rats. In addition, the microinjection of lidocaine into the ipsilateral locus coeruleus or the antagonism of the spinal α2-adrenergic receptors clearly reversed the effects of BVA on cold and mechanical hypersensitivity, indicating a vital role of the descending noradrenergic modulation in analgesia. These findings suggest that BVA could be a potential therapeutic option for vincristine-induced peripheral neuropathy.

Highlights

IntroductionVincristine, a derivative of Madagascar Catharanthus roseus (a species of flowering plant in the Apocynaceae family), is a core antineoplastic agent used to control the proliferation of lymphomas, acute lymphoblastic leukemia, and sarcomas [1]
Vincristine, a derivative of Madagascar Catharanthus roseus, is a core antineoplastic agent used to control the proliferation of lymphomas, acute lymphoblastic leukemia, and sarcomas [1]
The licking and shaking frequency of the hind paw in response to topical acetone application (10 μL) increased in the vincristine-treated group compared to the control group (p < 0.01, day 13; p < 0.001, days 16 to 25, Figure 1A)

Summary

Introduction

Vincristine, a derivative of Madagascar Catharanthus roseus (a species of flowering plant in the Apocynaceae family), is a core antineoplastic agent used to control the proliferation of lymphomas, acute lymphoblastic leukemia, and sarcomas [1]. Most cancer survivors experience progressive chemotherapy-induced peripheral neuropathy (CIPN) in the early stages of therapy or even years after the end of vincristine therapy [5]. Once this dose-limiting complication develops, Toxins 2020, 12, 775; doi:10.3390/toxins12120775 www.mdpi.com/journal/toxins. Natural compounds isolated from animals and plants represent a rich source of analgesics [7]. Bee venom (BV), a venomous mixture secreted from

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