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Suppressive Effects of Bee Venom Acupuncture on Paclitaxel-Induced Neuropathic Pain in Rats: Mediation by Spinal α₂-Adrenergic Receptor

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Suppressive Effects of Bee Venom Acupuncture on Paclitaxel-Induced Neuropathic Pain in Rats: Mediation by Spinal α₂-Adrenergic Receptor

Jiho Choi et al. Toxins (Basel).

Abstract

Paclitaxel, a chemotherapy drug for solid tumors, induces peripheral painful neuropathy. Bee venom acupuncture (BVA) has been reported to have potent analgesic effects, which are known to be mediated by activation of spinal α-adrenergic receptor. Here, we investigated the effect of BVA on mechanical hyperalgesia and spinal neuronal hyperexcitation induced by paclitaxel. The role of spinal α-adrenergic receptor subtypes in the analgesic effect of BVA was also observed. Administration of paclitaxel (total 8 mg/kg, intraperitoneal) on four alternate days (days 0, 2, 4, and 6) induced significant mechanical hyperalgesic signs, measured using a von Frey filament. BVA (1 mg/kg, ST36) relieved this mechanical hyperalgesia for at least two hours, and suppressed the hyperexcitation in spinal wide dynamic range neurons evoked by press or pinch stimulation. Both melittin (0.5 mg/kg, ST36) and phospholipase A2 (0.12 mg/kg, ST36) were shown to play an important part in this analgesic effect of the BVA, as they significantly attenuated the pain. Intrathecal pretreatment with the α₂-adrenergic receptor antagonist (idazoxan, 50 µg), but not α₁-adrenergic receptor antagonist (prazosin, 30 µg), blocked the analgesic effect of BVA. These results suggest that BVA has potent suppressive effects against paclitaxel-induced neuropathic pain, which were mediated by spinal α₂-adrenergic receptor.

Keywords: bee venom acupuncture; chemotherapy-induced neuropathic pain; paclitaxel.

Conflict of interest statement

The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Figures

Figure 1
Figure 1
Time course of paclitaxel-induced mechanical hyperalgesia. Rats were divided into two groups; paclitaxel (n = 7), vehicle (n = 7). Paclitaxel (2.0 mg/kg per injection) or vehicle was injected to rats four times (arrows; days 0, 2, 4 and 6). Significant differences between two groups were observed from the day 10 to day 21. Data are presented as mean ± SEM (* p < 0.05, ** p < 0.01; two-way ANOVA followed by Bonferroni’s multiple comparison test).
Figure 2
Figure 2
Effects of bee venom acupuncture (BVA) at different acupoints on paclitaxel-induced mechanical hyperalgesia. BVA (1.0 mg/kg) was used at (a) LI11 (n = 6) or (b) ST36 (n = 5) acupoints. In ST36 group, the paw withdrawal frequency (PWF) decreased significantly one or two hours after BVA, whereas no significant differences are shown in LI11 group. Data are presented as mean ± SEM (** p < 0.01, *** p < 0.001; repeated measures one-way ANOVA followed by Dunnett’s post hoc test).
Figure 3
Figure 3
Time course of the analgesic effect of BVA on paclitaxel-induced mechanical hyperalgesia. Rats were dispensed arbitrarily into two groups; paclitaxel + BVA (n = 7), paclitaxel + phosphate buffered saline (PBS) (n = 7). BVA (1.0 mg/kg) and PBS were treated at ST36. Significant reduction of PWF was observed from one to two hours after BVA. Data are presented as mean ± SEM (* p < 0.05, ** p < 0.01; two-way ANOVA followed by Bonferroni’s multiple comparison test).
Figure 4
Figure 4
Paclitaxel-induced hyperexcitation in wide dynamic range (WDR) neurons and inhibition of paclitaxel-induced hyperexcitation by BVA treatment. (ad) Representative extracellular recording raw traces of WDR neuron’s responses to pressing with hard stick (arrows, during 5 s) in vehicle group (a), paclitaxel group (b), and BVA (1 mg/kg) treated group (c,d). Before BVA treatment (c) and 30 min after BVA treatment (d). (e,f) The spike response of WDR neurons to mechanical stimulation (brush, press, and pinch). Data are presented as mean ± SEM (* p < 0.05, ** p < 0.01, *** p < 0.001; two-way ANOVA followed by Bonferroni’s multiple comparison test).
Figure 5
Figure 5
The analgesic effect of BVA, melittin, or PLA2 on paclitaxel-induced mechanical hyperalgesia. Rats showing signs of mechanical allodynia were dispensed arbitrarily into four groups; PBS (n = 7), BVA (1 mg/kg, n = 5), melittin (0.5 mg/kg, n = 6), and PLA2 (0.12 mg/kg, n = 7). All drugs were injected at ST36. PBS was used as control. Behavioral tests were conducted one hour after the drug administrations. Data are presented as mean ± SEM (** p < 0.01, *** p < 0.001; two-way ANOVA followed by Bonferroni’s multiple comparison test).
Figure 6
Figure 6
Effects of intrathecal adrenergic antagonists on BVA- or melittin-induced analgesic action. Rats were divided into six groups; (a) DMSO + BVA (n = 5), (b) prazosin + BVA (n = 5), (c) prazosin + melittin (n = 7), (d) PBS + BVA (n = 6), (e) idazoxan + BVA (n = 6), (f) idazoxan + melittin (n = 7). Data are presented as mean ± SEM (* p < 0.05, *** p < 0.001; paired t-test).
Figure 7
Figure 7
Time schedule of the experiment. (a) Paclitaxel was administered four alternate days (0, 2, 4, 6 days, i.p.); (b) the time course of BVA effect was conducted at 1, 2, 4, and 6 hours after administration of BVA; (c) antagonists were treated 20 min before administration of BVA or melittin, and behavior tests were conducted one hour after administration of BVA or melittin.

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