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

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.

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

“…for two 5-day cycles elicited noticeable cold and mechanical hypersensitivity in hind paws (Figure 1), which was consistent with other studies [19][20][21]. Major biological elements from BV have been shown to be efficacious for different painful deficits [7,[13][14][15][22][23][24]. Among the constituents, melittin (peptides) and bvPLA2 (enzymes) are the main bioactive ingredients of BV, representing 50% and 12% in dry weight, respectively [13,25].…”

“…Recently, our team reported that BVA, as one of the traditional mainstay methods for pain relief in East Asia, exerted remarkable effects in rodent models of peripheral neuropathy caused by taxanes or platinum-based anti-tumor substances [13][14][15]18]. Besides, the location specificity (acupoint vs. non-acupoint) of BV-induced analgesia has been determined in CIPN models [15]. In the current article, we demonstrate for the first time the ameliorative effect and mechanism of this pharmacopuncture therapy in vincristine-induced neuropathic signs in rats.…”

“…To date, the detailed analgesic features of acupuncture with purified BV or its main bioactive substances (e.g., melittin and bvPLA2) have been gradually studied in clinical diseases, such as osteoarthritis, musculoskeletal pain, and neuropathic pain [7,8,12]. Our earlier publications have reported that BV acupuncture (BVA) or administration of BV sub-components at ST36 (Zusanli) acupoint provided broad analgesia in oxaliplatin-or paclitaxel-induced neuropathic pain models, by selectively activating the spinal adrenergic receptors [13][14][15]. The descending noradrenergic system, which mainly originates in the locus coeruleus (LC, or A6), is the principal origin of endogenous pain modulation [16,17].…”

Bee Venom and Its Sub-Components: Characterization, Pharmacology, and Therapeutics

“…A total of 11 studies were published. Three reviews provided a good overview of the therapeutic effect of bee venom [ 6 , 7 , 8 ], and eight original research articles focused on bee venom, melittin, PLA 2 , and apamin [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

“…Lin and Hsieh [ 8 ] analyzed the anti-inflammatory, anti-apoptotic, and analgesic effects of bee venom injected at various acupoints. A study by Li et al [ 14 ] examined whether combined treatment with BVA and venlafaxine, a well-known serotonin and norepinephrine re-uptake inhibitor, could produce synergetic effects. They reported that the combined therapy resulted in long-lasting and additive anti-allodynic effects.…”