Long-Lasting and Additive Analgesic Effects of Combined Treatment of Bee Venom Acupuncture and Venlafaxine on Paclitaxel-Induced Allodynia in Mice.

Daxian Li,Ju Hyuk Yoo,Sun Kwang Kim

doi:10.3390/toxins12100620

Abstract

Paclitaxel, a primary chemotherapeutic agent used to treat numerous solid malignancies, is commonly associated with debilitating peripheral neuropathy. However, a satisfactory gold-standard monotherapy for this neuropathic pain is not currently available. A combination strategy of two or more medications with different properties may achieve more beneficial effects than monotherapy. Thus, we investigated the analgesic efficacies and spinal mechanisms of the combination strategy, including bee venom acupuncture (BVA) and venlafaxine (VLX) against paclitaxel-induced allodynia in mice. Four intraperitoneal infusions of paclitaxel on alternating days (2 mg/kg/day) induced cold and mechanical allodynia for at least 1 week as assessed using acetone and the von Frey hair test, respectively. Co-treatment of BVA (1.0 mg/kg, s.c., ST36) with VLX (40 mg/kg, i.p.) at the medium dose produced a longer-lasting and additive effect than each monotherapy at the highest dose (BVA, 2.5 mg/kg; VLX, 60 mg/kg). Spinal pre-administration of idazoxan (α2-adrenergic receptor antagonist, 10 μg), methysergide (mixed 5-HT1/5-HT2 receptor antagonist, 10 μg), or MDL-72222 (5-HT3 receptor antagonist, 10 μg) abolished this analgesia. These results suggest that the combination therapy with BVA and VLX produces long-lasting and additive analgesic effects on paclitaxel-induced allodynia, via the spinal noradrenergic and serotonergic mechanism, providing a promising clinical strategy.

Highlights

Paclitaxel, a derivative of Taxus brevifolia, is recommended worldwide as one of the standard antineoplastic medications against various types of carcinomas, including breast, lung, and ovarian cancers [1]
The highest dose group (2.5 mg/kg) showed a similar effect only at the 120 min time point. These results clearly demonstrate that bee venom acupuncture (BVA) treatment ameliorates cold and mechanical allodynia generated by paclitaxel, for which the optimum dosage is 1.0 mg/kg
We discovered that a single subcutaneous injection of Bee venom (BV) or its main components at ST36 clearly mitigates allodynic symptoms generated by paclitaxel or oxaliplatin, which are mainly associated with the spinal noradrenergic mechanisms [12,13]

Summary

Introduction

Paclitaxel, a derivative of Taxus brevifolia, is recommended worldwide as one of the standard antineoplastic medications against various types of carcinomas, including breast, lung, and ovarian cancers [1]. The representative clinical manifestations of this unwanted neuropathy include overt numbness, tingling, ongoing pain, and allodynia, most of which progress symmetrically from the feet and hands [3,4] This burdensome neurotoxic state can be sufficiently distressing to lead to temporary cessation or even termination of life-saving therapy, thereby affecting the survival likelihood [1,4]. There is an urgent need to identify favorable co-administration strategies for two or more medications that are already used in the clinic, which may offer considerable beneficial analgesia without unexpected adverse effects [6,7]

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Conclusion