• Animals
• Oxaliplatin/pharmacology
• Neuralgia/drug therapy
• Cisplatin/pharmacology
• Mice
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/chemical synthesis
• Prodrugs/pharmacology
• Prodrugs/chemistry
• Prodrugs/therapeutic use
• Prodrugs/chemical synthesis
• Organoplatinum Compounds/pharmacology
• Organoplatinum Compounds/chemistry
• Organoplatinum Compounds/therapeutic use
• Ganglia, Spinal/drug effects
• Ganglia, Spinal/metabolism
• Humans
• Cell Line, Tumor
• Male
• Paclitaxel/pharmacology
• Paclitaxel/therapeutic use

• Israel Cancer Research Fund
• Israel Science Foundation
• Israel Academy of Sciences and Humanities
• United States-Israel Binational Science Foundation
• National University of Singapore
• Clore Israel Foundation

• ostomy
• rectal cancer
• shared decision making
• sphincter-preservation

• ascites
• case report
• chemotherapy
• colorectal cancer
• oxaliplatin

• Natural Science Foundation of Jilin Province
• Jilin Province Development and Reform Commission

• GI cancer
• Long-term side effects
• Prevention

• Humans
• United States
• Aged
• Cancer Survivors
• Survivorship
• Survivors
• Colonic Neoplasms/drug therapy

• Assessment tool
• Oxaliplatin-induced peripheral neuropathy (OIPN)
• Patient-reported outcome
• Reliability and validity analysis
• Sensitivity

• Humans
• Oxaliplatin/adverse effects
• Antineoplastic Agents/adverse effects
• Neoplasms/drug therapy
• Reproducibility of Results
• Prospective Studies
• Quality of Life
• Peripheral Nervous System Diseases/chemically induced
• Peripheral Nervous System Diseases/diagnosis
• Peripheral Nervous System Diseases/drug therapy

• JD2019SZXYB02 Project of National Clinical Research Base of Traditional Chinese Medicine in Jiangsu Province
• JD2019SZXYB02 Project of National Clinical Research Base of Traditional Chinese Medicine in Jiangsu Province
• JD2019SZXYB02 Project of National Clinical Research Base of Traditional Chinese Medicine in Jiangsu Province
• CX10315 2022 Jiangsu Graduate Research and Practice Innovation Program
• Z2022005 Medical Scientific Research Project of Jiangsu Provincial Health Commission
• BE2019767 Jiangsu science and technology department social development-clinical frontier technology
• BE2019767 Jiangsu science and technology department social development-clinical frontier technology
• Project of Jiangsu Clinical Innovation Center of Digestive Cancer of Traditional Chinese Medicine

• Colorectal cancer
• adverse events
• supportive care
• tocotrienol
• toxicity

• Humans
• Adolescent
• Young Adult
• Adult
• Middle Aged
• Aged
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/pathology
• Oxaliplatin/therapeutic use
• Bevacizumab/adverse effects
• Tocotrienols/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Camptothecin
• Colonic Neoplasms/drug therapy
• Fluorouracil/adverse effects
• Rectal Neoplasms/drug therapy
• Leucovorin/adverse effects

• acupuncture
• chemotherapy
• colorectal cancer
• oxaliplatin
• peripheral neuropathy
• prevention

• Humans
• Single-Blind Method
• Neuroprotective Agents/adverse effects
• Acupuncture Therapy/adverse effects
• Peripheral Nervous System Diseases/chemically induced
• Peripheral Nervous System Diseases/prevention & control
• Antineoplastic Agents/adverse effects

• China Medical University Hospital
• Chinese Medicine Research Center
• Areas Research Center Program

• chemotherapy-induced peripheral neuropathy (CIPN)
• chemotherapy-induced toxicity
• neurotoxicity
• non-small cell lung cancer (NSCLC)
• platinum-based chemotherapy

• Humans
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• Platinum/adverse effects
• Prospective Studies
• Follow-Up Studies
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Peripheral Nervous System Diseases/chemically induced
• Peripheral Nervous System Diseases/genetics

• chemotherapy induced peripheral neuropathy
• gynecological cancer
• neurofilament light (NfL)
• neuropathy
• paclitaxel

• National Research Foundation of Korea

• CRC
• biomarker
• polyneuropathy
• rectal carcinoma
• screening

• antitumor activity
• chemotherapy
• estrogen receptors
• long-acting liposomes
• pharmacokinetics
• targeted drug delivery

Oxaliplatin-based therapy with FOLFOX-4 or CAPOX administered over 6 months remains the standard adjuvant treatment for stage III colon cancer (CC) patients. However, many patients experience dose reduction or early termination of chemotherapy due to oxaliplatin toxicity, which may increase the risk of early recurrence. The objective of this study was to analyze the relationship between the relative dose intensity of oxaliplatin (RDI-O) and early recurrence among stage III CC patients.

The study included 365 patients treated at five oncology centers in Poland between 2000 and 2014. Survival analysis was performed using the Kaplan-Meier method. Univariate analysis was performed using the Cox proportional hazard model; multivariate analysis was performed with the stepwise forward approach. For all analyses the α level of 0.05 was employed.

The median follow-up was 51.8 months (range 8.2–115.1). Early recurrence < 36 months after surgery occurred in 130 patients (37.8%). In this group 51 (39.2%) and 87 (66.9%) of patients were low and high-risk, respectively. Receipt < 60% of RDI-O was associated with early recurrence within 18 months after surgery (OR = 2.05; 95%CI: 1.18–3.51; p = 0.010), especially in low-risk group (HR = 1.56 (95%CI: 0.96–2.53), p = 0.07). In the multivariate analysis early recurrence was correlated with grade (OR = 2.47; 95% CI: 1.25–4.8; p = 0.008), pN (OR = 2.63; 95% CI: 1.55–4.54; p < 0.001), the number of lymph nodes harvested (OR = 0.51; 95% CI: 0.29–0.86; p = 0.013) and RDI-O (OR = 1.91; 95%CI: 1.06–3.39; p = 0.028). The early vs. late recurrence negatively correlated with OS regardless of the RDI-O (HR = 22.9 (95%CI: 13.9–37.6; p < 0.001).

RDI-O < 60% in adjuvant therapy among stage III CC (especially in low-risk group) increases the risk of early recurrence within 18 months of surgery. Patients with early recurrence showed worse overall survival regardless of the RDI-O.

• Adjuvant chemotherapy
• Colon cancer
• Cumulative dose
• Oxaliplatin
• Relative dose intensity

Peripheral neuropathy is a common and painful side effect that occurs in patients with cancer induced by Oxaliplatin (OXL). The neurotoxicity correlates with the damage of dorsal root ganglion (DRG) neurons and Schwann cells (SCs). Hydroxysafflor yellow A (HSYA), icariin, epimedin B and 3, 4-dihydroxybenzoic acid (DA) are the main neuroprotective ingredients identified in Wen-Luo-Tong (WLT), a traditional Chinese medicinal topical compound. The purpose of this study was to prepare and evaluate the efficacy of an ethosomes gel formulation loaded with a combination of HSYA, icariin, epimedin B and DA. However, the low LogP value, poor solubility and macromolecule are several challenges for topical delivery of these drugs.

Ethosomes were prepared by the single-step injection technique. Particle size, entrapment efficiency and in vitro drug deposition studies were determined to select the optimum ethosomes. The optimized ethosomes were further incorporated into carbopol to obtain a gel. The rheological properties, morphology, in vitro drug release, in vitro gel application and skin distribution of the ethosomes gels were studied. A rat model of oxaliplatin-induced neuropathy was established to assess the therapeutic efficacy of the ethosomes gel.

Seventy percent (v/v) ethanol, cinnamaldehyde and Phospholipon 90G were employed to develop ethosomes a carrier system. This system had a high entrapment efficiency, carried large amounts of HSYA, epimedin B, DA and icarrin, and penetrated deep into the epidermis and dermis. The optimized ethosomes had the maximum deposition of icariin, HSYA, epimedin B and relative higher amount of DA in epidermis (2.00±0.13 µg/cm², 5.72±0.75 µg/cm², 1.97±0.27 µg/cm² and 9.25±1.21 µg/cm², respectively). 0.5% carbopol 980 was selected to develop the ethosomes gel with desirable viscoelasticity and spreadability, which was suitable for topical application. The mechanical allodynia and hyperalgesia induced by OXL in rats were significantly reduced after the new ethosomes gel was applied to rats compared to model group.

Based on our findings, the ethosomes gel delivery system provided a new formulation for the topical delivery of HSYA, icariin, epimedin B and DA to counteract OXL-induced peripheral neuropathy.

• 3
• 4-dihydroxybenzoic acid
• DA
• epimedin B
• ethosomes gel
• hydroxysafflor yellow A
• icariin
• oxaliplatin-induced neuropathy

• Cipn
• lidocaine
• oxaliplatin

• Colorectal cancer
• Neuropathy
• Patient reported outcomes
• Quality of life

• Hepatocellular carcinoma
• Quality of life
• SF36
• Sorafenib
• TACE

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/psychology
• Carcinoma, Hepatocellular/therapy
• Chemoembolization, Therapeutic/mortality
• Cross-Sectional Studies
• Early Medical Intervention
• Female
• Follow-Up Studies
• Humans
• Liver Neoplasms/pathology
• Liver Neoplasms/psychology
• Liver Neoplasms/therapy
• Male
• Middle Aged
• Neoplasm Staging
• Prospective Studies
• Quality of Life
• Surveys and Questionnaires
• Survival Rate
• Treatment Outcome
• Young Adult

• Endothelin receptors
• Neuropathic pain
• Oxaliplatin
• Pain

• Animals
• Bosentan/administration & dosage
• Endothelin Receptor Antagonists
• Ganglia, Spinal/drug effects
• Ganglia, Spinal/metabolism
• Hyperalgesia/chemically induced
• Hyperalgesia/drug therapy
• Male
• Mice
• Oxaliplatin/toxicity
• Peripheral Nervous System Diseases/chemically induced
• Peripheral Nervous System Diseases/metabolism
• Receptor, Endothelin A/metabolism
• Receptor, Endothelin B/metabolism
• Spinal Cord Dorsal Horn/drug effects
• Spinal Cord Dorsal Horn/metabolism

• Colorectal cancer
• challenge
• treatment strategy

• Cancer survivors
• Cured
• Life-style
• late/long term side effects

Background. Peripheral neurotoxicity caused by oxaliplatin (OXA) chemotherapy is the main limitation preventing continuation of chemotherapy in patients with gastrointestinal cancer. The purpose of this study was to determine the efficacy of external use of Chinese herbal medicine (CHM) on the incidence of cumulative OXA-induced peripheral neurotoxicity (OIPN). Method. Scientific literature databases were searched to identify controlled clinical trials analyzing CHM in OIPN. Clinical studies that included at least 1 relevant primary outcome were analyzed by 2 independent reviewers. Meta-analysis was performed on the software RevMan 5.3. Results. 700 cancer patients of 9 studies were reported, of whom 352 received external CHM and 348 received warm water baths, conventional medicine, or no intervention as controls. Neurotoxicity incidence (Levi grade ≥ 1) was significantly decreased in CHM group, compared with no intervention (P < .01). The incidence of cumulative neurotoxicity (Levi grade ≥2) was also significantly lower in the CHM group than in all the control groups (P < .05), and the cumulative neurotoxicity in the CHM group was significantly reduced (Levi grade ≥ 3) in comparision with no intervention (P < .01). These results were consistent with those of the subgroup analyses for preventing OIPN at each of the chemotherapy treatment cycles. There was no difference in the incidence of adverse events between groups (P > .05). Conclusion. External use of CHM may be beneficial in preventing the OXA-induced cumulative neurotoxicity. However, given the low quality of the evidence, the results should be interpreted with caution.

• Colorectal cancer
• Metformin
• Oxaliplatin
• Peripheral neuropathy

• Chemotherapy
• Chimiothérapie
• Douleur
• Neuropathie périphérique
• Pain
• Peripheral neuropathy
• Quality of life
• Qualité de vie

• Adverse effects
• Chemotherapy
• Colorectal cancer
• MR309/E-52862
• Neuropathic pain
• Neurotoxicity

• Adult
• Aged
• Antineoplastic Agents/adverse effects
• Colorectal Neoplasms/complications
• Colorectal Neoplasms/drug therapy
• Double-Blind Method
• Female
• Humans
• Male
• Middle Aged
• Morpholines/therapeutic use
• Oxaliplatin/adverse effects
• Pain Threshold/drug effects
• Peripheral Nervous System Diseases/chemically induced
• Peripheral Nervous System Diseases/drug therapy
• Pyrazoles/therapeutic use
• Receptors, sigma/antagonists & inhibitors
• Treatment Outcome
• Young Adult
• Sigma-1 Receptor

• Oxaliplatin
• single nucleotide polymorphisms
• peripheral neuropathy
• sodium channels
• cancer

• Peripheral neuropathy
• UPLC-Q-TOF/MS
• W/O Wen-Luo-Tong microemulsion
• dorsal root ganglion
• hydroxysafflor yellow A
• icarrin
• mechanical allodynia
• schwann cells

• Chemotherapy
• Complication
• Duration
• FOLFOX
• Oxaliplatin
• Survival

• Cold allodynia
• Mechanical hyperalgesia
• Oxaliplatin-induced peripheral neuropathy
• Substance P
• Therapeutic ultrasound
• Transient receptor potential channels

• Animals
• Cold Temperature
• Hyperalgesia/chemically induced
• Hyperalgesia/physiopathology
• Hyperalgesia/therapy
• Male
• Organoplatinum Compounds
• Oxaliplatin
• Pain Measurement
• Peroneal Nerve/physiopathology
• Rats
• Rats, Sprague-Dawley
• Sural Nerve/physiopathology
• Touch
• Treatment Outcome
• Ultrasonic Therapy/methods

The antineoplastic agent oxaliplatin induces a painful peripheral neuropathy characterized by an acute cold hypersensitivity. There is a lack of effective treatments to manage oxaliplatin-induced cold hypersensitivity which is due, in part, to a lack of understanding of the pathophysiology of oxaliplatin-induced cold hypersensitivity. Thus, brain activity in oxaliplatin-treated macaques was examined using functional magnetic resonance imaging (fMRI). Oxaliplatin treatment reduced tail withdrawal latency to a cold (10 °C) stimulus, indicating cold hypersensitivity and increased activation in the secondary somatosensory cortex (SII) and the anterior insular cortex (Ins) was observed. By contrast, no activation was observed in these areas following cold stimulation in untreated macaques. Systemic treatment with an antinociceptive dose of the serotonergic-noradrenergic reuptake inhibitor duloxetine decreased SII and Ins activity. Pharmacological inactivation of SII and Ins activity by microinjection of the GABA_A receptor agonist muscimol increased tail withdrawal latency. The current findings indicate that SII/Ins activity is a potential mediator of oxaliplatin-induced cold hypersensitivity.

• FOLFOX
• colorectal cancer
• neuropathy
• neurotoxicity
• oxaliplatin

Neurotoxic anticancer drugs, such as platinum-based anticancer drugs, taxanes, vinca alkaloids, and proteasome/angiogenesis inhibitors are responsible for chemotherapy-induced peripheral neuropathy (CIPN). The health consequences of CIPN remain worrying as it is associated with several comorbidities and affects a specific population of patients already impacted by cancer, a strong driver for declines in older adults. The purpose of this review is to present a comprehensive overview of the long-term effects of CIPN in cancer patients and survivors. Pathophysiological mechanisms and risk factors are also presented. Neurotoxic mechanisms leading to CIPNs are not yet fully understood but involve neuronopathy and/or axonopathy, mainly associated with DNA damage, oxidative stress, mitochondria toxicity, and ion channel remodeling in the neurons of the peripheral nervous system. Classical symptoms of CIPNs are peripheral neuropathy with a “stocking and glove” distribution characterized by sensory loss, paresthesia, dysesthesia and numbness, sometimes associated with neuropathic pain in the most serious cases. Several risk factors can promote CIPN as a function of the anticancer drug considered, such as cumulative dose, treatment duration, history of neuropathy, combination of therapies and genetic polymorphisms. CIPNs are frequent in cancer patients with an overall incidence of approximately 38% (possibly up to 90% of patients treated with oxaliplatin). Finally, the long-term reversibility of these CIPNs remain questionable, notably in the case of platinum-based anticancer drugs and taxanes, for which CIPN may last several years after the end of anticancer chemotherapies. These long-term effects are associated with comorbidities such as depression, insomnia, falls and decreases of health-related quality of life in cancer patients and survivors. However, it is noteworthy that these long-term effects remain poorly studied, and only limited data are available such as in the case of bortezomib and thalidomide-induced peripheral neuropathy.

• anticancer drugs
• chemotherapy-induced peripheral neuropathy
• long-term effects
• pathophysiological mechanisms
• risk factors

• Oxaliplatin
• Peripheral nervous system diseases
• Psychometrics
• Symptom assessment

Oxaliplatin is a first‐line treatment for colorectal cancer. However, shortly following treatment, cold‐evoked hypersensitivity appears in the extremities and over time, the pain is such that oxaliplatin dosing may need to be markedly reduced or even terminated. There is currently a lack of efficacious treatments for oxaliplatin‐induced peripheral neuropathy, which is due in part to the difficulty in translating findings obtained from preclinical rodent models of chemotherapy‐induced peripheral neuropathy. Nonhuman primates (NHP) are phylogenetically closer to humans than rodents and may show drug responses that parallel those of humans. A significant decrease in tail withdrawal latency to 10°C water (“cold hypersensitivity”) was observed beginning 3 days after intravenous infusion of oxaliplatin (5 mg/kg) in Macaca fascicularis. A single treatment of duloxetine (30 mg/kg, p.o.) ameliorated oxaliplatin‐induced cold hypersensitivity, whereas pregabalin (30 mg/kg, p.o.) and tramadol (30 mg/kg, p.o.) did not. By contrast, in rats, no significant cold hypersensitivity, or increased responsiveness to acetone applied to the hind paws, was observed 3 days after the first injection of oxaliplatin (5 mg/kg, i.p., once per day, two injections). Therefore, rats were tested after six treatments of oxaliplatin, 17 days after the first treatment. All analgesics (30 mg/kg, p.o.) significantly ameliorated cold hypersensitivity in rats. The activity of analgesics in the oxaliplatin‐treated macaques parallel clinical findings. The current results indicate that the NHP could serve as a bridge species to improve translatability of preclinical findings into clinically useful treatments for oxaliplatin‐induced peripheral neuropathy.

• Chemotherapy‐induced peripheral neuropathy
• Macaca fascicularis
• cold hypersensitivity
• duloxetine
• preclinical translation
• pregabalin
• tramadol

• cold allodynia
• oxaliplatin
• pain
• peripheral neuropathy
• thermal grill

A 66-year-old female presented with the main complaint of defecation trouble and abdominal distention. With diagnosis of rectal cancer, cSS, cN0, cH0, cP0, cM0 cStage II, Hartmann’s operation with D3 lymph node dissection was performed and a para-aortic lymph node and a disseminated node near the primary tumor were resected. Histological examination showed moderately differentiated adenocarcinoma, pSS, pN3, pH0, pP1, pM1 (para-aortic lymph node, dissemination) fStage IV. After the operation, the patient received chemotherapy with FOLFIRI regimen. After 12 cycles of FOLFIRI regimen, computed tomography (CT) detected an 11 mm of liver metastasis in the postero-inferior segment of right hepatic lobe. With diagnosis of liver metastatic recurrence, we performed partial hepatectomy. Histological examination revealed moderately differentiated adenocarcinoma as a metastatic rectal cancer with cut end microscopically positive. After the second operation, the patient received chemotherapy with TS1 alone for 2 years. Ten months after the break, CT detected a 20 mm of para-aortic lymph node metastasis and a 10 mm of lymph node metastasis at the hepato-duodenal ligament. With diagnosis of lymph node metastatic recurrences, we performed lymph node dissection. Histological examination revealed moderately differentiated adenocarcinoma as metastatic rectal cancer in para-aortic and hepato-duodenal ligament areas. After the third operation, we started chemotherapy with modified FOLFOX6 regimen. After 2 cycles of modified FOLFOX6 regimen, due to the onset of neutropenia and liver dysfunction, we switched to capecitabine alone and continued it for 6 mo and then stopped. Eleven months after the break, CT detected two swelling 12 mm of lymph nodes at the left supraclavicular region. With diagnosis of Virchow lymph node metastatic recurrence, we started chemotherapy with capecitabine plus bevacizumab regimen. Due to the onset of neutropenia and hand foot syndrome (Grade 3), we managed to continue capecitabine administration with extension of interval period and dose reduction. After 2 years and 2 mo from starting capecitabine plus bevacizumab regimen, Virchow lymph nodes had slowly grown up to 17 mm. Because no recurrence had been detected besides Virchow lymph nodes for this follow up period, considering the side effects and quality of life, surgical resection was selected. We performed left supraclavicular lymph node dissection. Histological examination revealed moderately differentiated adenocarcinoma as a metastatic rectal cancer. After the fourth operation, the patient selected follow up without chemotherapy. Now we follow up her without recurrence and keep her quality of life high.

• Rectal cancer
• Surgical resection
• Virchow lymph node metastasis
• Para-aortic lymph node metastasis
• Liver metastasis
• Peritoneal carcinomatosis
• Long-term survival

• Adenocarcinoma/secondary
• Adenocarcinoma/surgery
• Aged
• Chemotherapy, Adjuvant
• Female
• Hepatectomy
• Humans
• Liver Neoplasms/secondary
• Liver Neoplasms/surgery
• Lymph Node Excision
• Lymph Nodes/pathology
• Lymph Nodes/surgery
• Lymphatic Metastasis
• Neoplasm Staging
• Positron-Emission Tomography
• Rectal Neoplasms/pathology
• Rectal Neoplasms/surgery
• Time Factors
• Tomography, X-Ray Computed
• Treatment Outcome

• End Results (SEER) program
• Surveillance, Epidemiology
• aged
• colon cancer
• colonic neoplasms/therapy
• community-institutional relations
• health care disparities
• oxaliplatin

• Black or African American
• Aged
• Aged, 80 and over
• Antineoplastic Agents/therapeutic use
• Cohort Studies
• Colonic Neoplasms/drug therapy
• Colonic Neoplasms/ethnology
• Colonic Neoplasms/pathology
• Community Networks/organization & administration
• Female
• Health Services Accessibility
• Healthcare Disparities/statistics & numerical data
• Humans
• Male
• National Cancer Institute (U.S.)/organization & administration
• Organoplatinum Compounds/therapeutic use
• Oxaliplatin
• Retrospective Studies
• United States

• HHSN261200800726P NCI NIH HHS
• T32 CA128590 NCI NIH HHS
• T32 NR008856 NINR NIH HHS
• 5R01CA124402 NCI NIH HHS
• 5T32CA128590-04 NCI NIH HHS
• 2T32NR008856 NINR NIH HHS
• R01 CA124402 NCI NIH HHS
• HHSN-261200800726P PHS HHS

Oxaliplatin, 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.

The 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.

The 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-HT_1A receptor antagonist, 15 μg, i.t.) or ketanserin (5-HT_2A receptor antagonist, 30 μg, i.t.) did not.

These 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.