The Serotonin-Mediated Anti-Allodynic Effect of Yokukansan on Paclitaxel-Induced Neuropathic Pain

Abstract

Refractory peripheral neuropathy can occur as a side effect in 60–70% of patients receiving Paclitaxel (PTX). Yokukansan (YKS) is a Japanese herbal medicine reported to have analgesic properties for entrapment nerve injuries. Therefore, we investigated the anti-allodynic effect of Yokukansan on Paclitaxel-induced neuropathic pain. All experiments used 6-week-old male Sprague Dawley rats. Mechanical allodynia was evaluated using a dynamic plantar aesthesiometer. A mobile touch-stimulator unit applied progressively increasing force to the mid-plantar region of the hind paw in a vertical direction until the animal withdrew its paw. This was carried out before the Paclitaxel administration and during the first, second, third, and fourth weeks. Using a rat model of PTX-induced neuropathic pain (PTX rat), we injected PTX (intraperitoneally, 2 mg/kg) five times every 2 days. Using the dynamic plantar test, we evaluated the anti-allodynic effect of YKS (orally administered, 1 g/kg). YKS administration on a daily basis significantly enhanced the withdrawal threshold in PTX rats and reduced the expression level of activated microglia immunostaining with Iba1, a specific marker for microglia. The intrathecal administration of WAY-100635 (5-hydroxytryptamine [5-HT]1A receptor antagonist) and Ketanserin (5-HT2A/2C receptor antagonist) inhibited the protective effects of YKS. YKS exhibited an anti-allodynic effect in a rodent model of PTX-induced neuropathic pain by reducing the sensitivity to pain stimuli. These results suggest that Yokukansan may activate 5-HT receptors in the spinal cord, mediating Paclitaxel-induced neuropathic pain.

Phytoconstituents Targeting the Serotonin 5-HT3 Receptor: Promising Therapeutic Strategies for Neurological Disorders

“…These rats were treated with the standard drug, 60 μg of WAY100635 (a 5-HT 1A receptor antagonist) or 30 μg of ketanserin (a 5-TH 2A/2C receptor antagonist) or 30 μg of ondansetron (a 5-HT 3 R antagonist) or test drug Yokukansan, a Japanese medicine containing seven traditional mixture. Yokukansan attenuated PTX side effects by acting on the 5-HT 1 and 5HT 2 receptor and less via 5-HT 3 R. It improved allodynia and increased the withdrawal threshold, which supports its therapeutic use in neuropathic pain via 5HT 1 , 5-HT 2 , and 5-HT 3 R . Grape seed extract (GSE) was evaluated for action by 5-HT 3 and GABA receptors in temporomandibular disorders characterized by dysfunctional jaw joints and muscles that control jaw movement.…”