Abstract
BackgroundOxaliplatin, an important chemotherapy drug for advanced colorectal cancer, often induces peripheral neuropathy, especially cold allodynia. Our previous study showed that bee venom acupuncture (BVA), which has been traditionally used in Korea to treat various pain symptoms, potently relieves oxaliplatin-induced cold allodynia in rats. However, the mechanism for this anti-allodynic effect of BVA remains poorly understood. We investigated whether and how the central serotonergic system, a well-known pathway for acupuncture analgesia, mediates the relieving effect of BVA on cold allodynia in oxaliplatin-injected rats.MethodsThe behavioral signs of cold allodynia in Sprague–Dawley (SD) rats were induced by a single injection of oxaliplatin (6 mg/kg, i.p.). Before and after BVA treatment, the cold allodynia signs were evaluated by immersing the rat’s tail into cold water (4°C) and measuring the withdrawal latency. For BVA treatment, a diluted BV (0.25 mg/kg) was subcutaneously administered into Yaoyangguan (GV3) acupoint, which is located between the spinous processes of the fourth and the fifth lumbar vertebra. Serotonin was depleted by a daily injection of DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.) for 3 days. The amount of serotonin in the spinal cord was measured by ELISA. Serotonergic receptor antagonists were administered intraperitoneally or intrathecally before BVA treatment.ResultsThe serotonin levels in the spinal cord were significantly increased by BVA treatment and such increase was significantly reduced by PCPA. This PCPA pretreatment abolished the relieving effect of BVA on oxaliplatin-induced cold allodynia. Either of methysergide (mixed 5-HT1/5-HT2 receptor antagonist, 1 mg/kg, i.p.) or MDL-72222 (5-HT3 receptor antagonist, 1 mg/kg, i.p) blocked the anti-allodynic effect of BVA. Further, an intrathecal injection of MDL-72222 (12 μg) completely blocked the BVA-induced anti-allodynic action, whereas NAN-190 (5-HT1A receptor antagonist, 15 μg, i.t.) or ketanserin (5-HT2A receptor antagonist, 30 μg, i.t.) did not.ConclusionsThese results suggest that BVA treatment alleviates oxaliplatin-induced acute cold allodynia in rats via activation of the serotonergic system, especially spinal 5-HT3 receptors. Thus, our findings may provide a clinically useful evidence for the application of BVA as an alternative therapeutic option for the management of peripheral neuropathy, a dose-limiting side effect that occurs after an administration of oxaliplatin.
Highlights
Oxaliplatin, an important chemotherapy drug for advanced colorectal cancer, often induces peripheral neuropathy, especially cold allodynia
In our recent study [16], we showed that bee venom acupuncture (BVA) (0.25 mg/kg) treatment at Yaoyangguan (GV3) acupoint significantly attenuated oxaliplatin-induced cold allodynia in rats, which was greater than BVA treatment at the other well-known acupoints for acupuncture analgesia (e.g. Zusanli [ST36] and Quchi [LI11])
Effects of 5-HT depletion with PCPA on BVA-induced anti-allodynia in oxaliplatin-injected rats To determine whether the serotonergic system is involved in the anti-allodynic effect of BVA, we evaluated the effect of depletion of central 5-HT by PCPA on the BVA effect
Summary
Oxaliplatin, an important chemotherapy drug for advanced colorectal cancer, often induces peripheral neuropathy, especially cold allodynia. The most important side effect of oxaliplatin treatment is a peripheral neuropathy that has unique characteristics and represents a major dose-limiting toxicity [3,4]. This unpleasant acute neurosensory toxicity with dysesthesia of the distal extremities and perioral region occurs shortly after an infusion in as much as 90% of the patients. The mechanisms and the effective treatment for oxaliplatininduced cold allodynia still remain to be elucidated [8] It is worth searching for potential therapeutic options for the management of oxaliplatin-induced neuropathic pain and revealing their action mechanisms
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