Journal articles: 'Oxaliplatin-induced neuropathic pain'

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Hama, Aldric, Takahiro Natsume, Shin’ya Ogawa, Noriyuki Higo, Ikuo Hayashi, and Hiroyuki Takamatsu. "Gaps in Understanding Mechanism and Lack of Treatments: Potential Use of a Nonhuman Primate Model of Oxaliplatin-Induced Neuropathic Pain." Pain Research and Management 2018 (May 2, 2018): 1–11. http://dx.doi.org/10.1155/2018/1630709.

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The antineoplastic agent oxaliplatin induces an acute hypersensitivity evoked by cold that has been suggested to be due to sensitized central and peripheral neurons. Rodent-based preclinical studies have suggested numerous treatments for the alleviation of oxaliplatin-induced neuropathic pain, but few have demonstrated robust clinical efficacy. One issue is that current understanding of the pathophysiology of oxaliplatin-induced neuropathic pain is primarily based on rodent models, which might not entirely recapitulate the clinical pathophysiology. In addition, there is currently no objective physiological marker for pain that could be utilized to objectively indicate treatment efficacy. Nonhuman primates are phylogenetically and neuroanatomically similar to humans; thus, disease mechanism in nonhuman primates could reflect that of clinical oxaliplatin-induced neuropathy. Cold-activated pain-related brain areas in oxaliplatin-treated macaques were attenuated with duloxetine, the only drug that has demonstrated clinical efficacy for chemotherapy-induced neuropathic pain. By contrast, drugs that have not demonstrated clinical efficacy in oxaliplatin-induced neuropathic pain did not reduce brain activation. Thus, a nonhuman primate model could greatly enhance understanding of clinical pathophysiology beyond what has been obtained with rodent models and, furthermore, brain activation could serve as an objective marker of pain and therapeutic efficacy.

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Kato, Natsuki, Keisuke Tateishi, Masanobu Tsubaki, Tomoya Takeda, Mikihiro Matsumoto, Katsumasa Tsurushima, Toshihiko Ishizaka, and Shozo Nishida. "Gabapentin and Duloxetine Prevent Oxaliplatin- and Paclitaxel-Induced Peripheral Neuropathy by Inhibiting Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Phosphorylation in Spinal Cords of Mice." Pharmaceuticals 14, no. 1 (December 31, 2020): 30. http://dx.doi.org/10.3390/ph14010030.

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Chemotherapy-induced peripheral neuropathy is a common factor in limiting therapy which can result in therapy cessation or dose reduction. Gabapentin, a calcium channel inhibitor, and duloxetine, a serotonin noradrenaline reuptake inhibitor, are used to treat a variety of pain conditions such as chronic low back pain, postherpetic neuralgia, and diabetic neuropathy. It has been reported that administration of gabapentin suppressed oxaliplatin- and paclitaxel-induced mechanical hyperalgesia in rats. Moreover, duloxetine has been shown to suppress oxaliplatin-induced cold allodynia in rats. However, the mechanisms by which these drugs prevent oxaliplatin- and paclitaxel-induced neuropathy remain unknown. Behavioral assays were performed using cold plate and the von Frey test. The expression levels of proteins were examined using western blot analysis. In this study, we investigated the mechanisms by which gabapentin and duloxetine prevent oxaliplatin- and paclitaxel-induced neuropathy in mice. We found that gabapentin and duloxetine prevented the development of oxaliplatin- and paclitaxel-induced cold and mechanical allodynia. In addition, our results revealed that gabapentin and duloxetine suppressed extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation in the spinal cord of mice. Moreover, PD0325901 prevented the development of oxaliplatin- and paclitaxel-induced neuropathic-like pain behavior by inhibiting ERK1/2 activation in the spinal cord of mice. In summary, our findings suggest that gabapentin, duloxetine, and PD0325901 prevent the development of oxaliplatin- and paclitaxel-induced neuropathic-like pain behavior by inhibiting ERK1/2 phosphorylation in mice. Therefore, inhibiting ERK1/2 phosphorylation could be an effective preventive strategy against oxaliplatin- and paclitaxel-induced neuropathy.

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Lee, Ji Hwan, and Woojin Kim. "Involvement of Serotonergic System in Oxaliplatin-Induced Neuropathic Pain." Biomedicines 9, no. 8 (August 6, 2021): 970. http://dx.doi.org/10.3390/biomedicines9080970.

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Oxaliplatin is a chemotherapeutic agent widely used against colorectal and breast cancers; however, it can also induce peripheral neuropathy that can rapidly occur even after a single infusion in up to 80–90% of treated patients. Numerous efforts have been made to understand the underlying mechanism and find an effective therapeutic agent that could diminish pain without damaging its anti-tumor effect. However, its mechanism is not yet clearly understood. The serotonergic system, as part of the descending pain inhibitory system, has been reported to be involved in different types of pain. The malfunction of serotonin (5-hydroxytryptamine; 5-HT) or its receptors has been associated with the development and maintenance of pain. However, its role in oxaliplatin-induced neuropathy has not been clearly elucidated. In this review, 16 in vivo studies focused on the role of the serotonergic system in oxaliplatin-induced neuropathic pain were analyzed. Five studies analyzed the involvement of 5-HT, while fourteen studies observed the role of its receptors in oxaliplatin-induced allodynia. The results show that 5-HT is not involved in the development of oxaliplatin-induced allodynia, but increasing the activity of the 5-HT1A, 5-HT2A, and 5-HT3 receptors and decreasing the action of 5-HT2C and 5-HT6 receptors may help inhibit pain.

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Gebremedhn, Endale G., Peter J. Shortland, and David A. Mahns. "Variability of Oxaliplatin-Induced Neuropathic Pain Symptoms in Each Cycle and Its Implications on the Management of Colorectal Cancer Patients: A Retrospective Study in South Western Sydney Local Health District Hospitals, Sydney, Australia." Journal of Oncology 2019 (August 1, 2019): 1–11. http://dx.doi.org/10.1155/2019/4828563.

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Oxaliplatin-induced neuropathic pain limits treatment compliance. However, the variability of neuropathic pain symptoms in each cycle for individual patients and the impacts on treatment compliance remain untested. Data from 322 adult patients who received oxaliplatin-based chemotherapy were extracted based on pattern of chemotherapy, adverse events, and patient survival. Cox regression and survival analyses were employed. Seventy-eight percent of patients developed neuropathic pain that oscillated between a complete absence and presence on a cycle-by-cycle basis. Consequently, the presence of neuropathy in one cycle did not predict the incidence of neuropathy in subsequent cycles. This implies that neuropathic pain need not be a sufficient criterion to reduce, delay, or cease chemotherapy. In the case of multiple system adverse events during combined drug treatment, the responsible cause for dose reduction was not identified. Cox regression analysis revealed that middle age (61–78 years old,P=0.003) and oxaliplatin cumulative dose <850 mg/m2(P=0.002) were associated with patient mortality. Completion of chemotherapy (8 cycles) and cumulative dose >850 mg/m2of oxaliplatin prolonged the median survival time by 8 and 5 months, respectively. As oxaliplatin-induced neuropathic pain fluctuates across cycles in a manner that varies from patient-to-patient, current assumptions on the predictive nature of the emergence of neuropathy (and its impact on treatment compliance) need to be reconsidered. Detailed patient-by-patient analysis of adverse events should be applied to future studies in order to determine the efficacy of current treatments (and future interventions) and whether neuropathic pain should be retained as a criterion to vary the treatment. Additionally, when two or more system toxicities occurred in cases of combined drug treatment, the causes for drug reduction should be separately recorded.

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Ling, Jennifer, Ferhat Erol, Viacheslav Viatchenko-Karpinski, Hirosato Kanda, and Jianguo G. Gu. "Orofacial neuropathic pain induced by oxaliplatin." Molecular Pain 13 (January 2017): 174480691772471. http://dx.doi.org/10.1177/1744806917724715.

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Lopes, Arthur, Kleber Duarte, Catarina Lins, Gabriel Kubota, Valquíria Silva, Ricardo Galhardoni, Luciana Mendes Bahia Menezes, Irina Raicher, Manoel J. Teixeira, and Daniel C. Andrade. "Spinal Cord Stimulation as a Treatment Option for Refractory Chemotherapy-Induced Peripheral Neuropathy: Case Report." Arquivos Brasileiros de Neurocirurgia: Brazilian Neurosurgery 39, no. 03 (June 23, 2020): 228–31. http://dx.doi.org/10.1055/s-0040-1709985.

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AbstractColorectal cancer is one of the most common oncological diseases. Chemotherapy is usually recommended as an adjuvant treatment for stage-II, -III, and -IV tumors. Approximately 10% of the patients develop neuropathic pain after chemotherapy, and they may remain refractory despite the administration of drugs that are commonly used to treat neuropathic pain. Spinal cord stimulation is a good treatment option for neuropathic pain of the lower limbs, and it should be trialed in patients with chemotherapy-induced peripheral neuropathy. We report the case of a patient with oxaliplatin-induced neuropathy and neuropathic pain refractory to oral medication who was successfully treated by spinal cord stimulation.

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Delmotte, Jean-Baptiste, Abdulkarim Tutakhail, Kahina Abdallah, Pauline Reach, Marguerite D’Ussel, Gael Deplanque, Hélène Beaussier, and François Coudoré. "Electrochemical Skin Conductance as a Marker of Painful Oxaliplatin-Induced Peripheral Neuropathy." Neurology Research International 2018 (September 27, 2018): 1–9. http://dx.doi.org/10.1155/2018/1254602.

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Purpose. Oxaliplatin is a platinum compound widely used in gastrointestinal cancer treatment but produces dose-limiting peripheral neuropathy. New insights into oxaliplatin-induced peripheral neuropathy (OIPN) assessment are needed to detect more effectively this condition. In this context, we conducted Canaloxa study, a prospective preliminary clinical trial that aimed to investigate how Electrochemical Skin Conductance (ESC), a parameter used in small fiber neuropathy assessment, could be helpful in OIPN diagnosis. Methods. Cancer patients treated for at least three months with oxaliplatin and suffering from clinically OIPN were included. Electrochemical Skin Conductance, thermal thresholds, and neuropathic pain were assessed in all included patients. Results. During one year, 36 patients were included. The main result was the correlation between ESC and Neuropathic Pain Symptom Inventory score for hands (rho value = -0.69, p < 0.0001) and feet (rho value = -0.79, p < 0.0001). ESC values were lower in neuropathic patients with painful symptoms than in ones without painful symptoms (p = 0.0003 and p < 0.0001 for hands and feet, respectively). No correlation was observed between ESC and thermal thresholds. Conclusion. These preliminary data suggest that ESC could be a useful objective marker of painful oxaliplatin-induced neuropathy and could complement the use of subjective clinical scales. This study was prospectively registered on clinicaltrials.gov (NCT02827916) before patient recruitment has begun.

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Lee, Ji Hwan, Hyunseung Ji, Seong-Gyu Ko, and Woojin Kim. "JI017 Attenuates Oxaliplatin-Induced Cold Allodynia via Spinal TRPV1 and Astrocytes Inhibition in Mice." International Journal of Molecular Sciences 22, no. 16 (August 16, 2021): 8811. http://dx.doi.org/10.3390/ijms22168811.

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Oxaliplatin, a well-known chemotherapeutic agent, can induce severe neuropathic pain, which can seriously decrease the quality of life of patients. JI017 is an herb mixture composed of Aconitum carmichaelii, Angelica gigas, and Zingiber officinale. Its anti-tumor effect has been reported; however, the efficacy of JI017 against oxaliplatin-induced allodynia has never been explored. Single oxaliplatin injection [6 mg/kg, intraperitoneal, (i.p.)] induced both cold and mechanical allodynia, and oral administration of JI017 (500 mg/kg) alleviated cold but not mechanical allodynia in mice. Real-time polymerase chain reaction (PCR) analysis demonstrated that the upregulation of mRNA of spinal transient receptor potential vanilloid 1 (TRPV1) and astrocytes following oxaliplatin injection was downregulated after JI017 treatment. Moreover, TRPV1 expression and the activation of astrocytes were intensely increased in the superficial area of the spinal dorsal horn after oxaliplatin treatment, whereas JI017 suppressed both. The administration of TRPV1 antagonist [capsazepine, intrathecal (i.t.), 10 μg] attenuated the activation of astrocytes in the dorsal horn, demonstrating that the functions of spinal TRPV1 and astrocytes are closely related in oxaliplatin-induced neuropathic pain. Altogether, these results suggest that JI017 may be a potent candidate for the management of oxaliplatin-induced neuropathy as it decreases pain, spinal TRPV1, and astrocyte activation.

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Di Cesare Mannelli, Lorenzo, Alessandra Pacini, Laura Micheli, Alessia Tani, Matteo Zanardelli, and Carla Ghelardini. "Glial role in oxaliplatin-induced neuropathic pain." Experimental Neurology 261 (November 2014): 22–33. http://dx.doi.org/10.1016/j.expneurol.2014.06.016.

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Wang, Huanbai, Xiaodan Li, Dongting Zhangsun, Gang Yu, Ruibin Su, and Sulan Luo. "The α9α10 Nicotinic Acetylcholine Receptor Antagonist αO-Conotoxin GeXIVA[1,2] Alleviates and Reverses Chemotherapy-Induced Neuropathic Pain." Marine Drugs 17, no. 5 (May 5, 2019): 265. http://dx.doi.org/10.3390/md17050265.

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Oxaliplatin is a third-generation platinum drug and is widely used as a first-line therapy for the treatment of colorectal cancer (CRC). However, a large number of patients receiving oxaliplatin develop dose-limiting painful neuropathy. Here, we report that αO-conotoxin GeXIVA[1,2], a highly potent and selective antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype, can relieve and reverse oxaliplatin-induced mechanical and cold allodynia after single and repeated intramuscular (IM) injections in rats. Treatments were started at 4 days post oxaliplatin injection when neuropathic pain emerged and continued for 8 and 16 days. Cold score and mechanical paw withdrawal threshold (PWT) were detected by the acetone test and von Frey test respectively. GeXIVA[1,2] significantly relieved mechanical and cold allodynia in oxaliplatin-treated rats after a single injection. After repeated treatments, GeXIVA[1,2] produced a cumulative analgesic effect without tolerance and promoted recovery from neuropathic pain. Moreover, the long lasting analgesic effect of GeXIVA[1,2] on mechanical allodynia continued until day 10 after the termination of the 16-day repeated treatment procedure. On the contrary, GeXIVA[1,2] did not affect acute mechanical and thermal pain behaviors in normal rats after repeated injections detected by the von Frey test and tail flick test. GeXIVA[1,2] had no influence on rat hind limb grip strength and body weight after repeated treatments. These results indicate that αO-conotoxin GeXIVA[1,2] could provide a novel strategy to treat chemotherapy-induced neuropathic pain.

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Lee, Ji Hwan, and Woojin Kim. "The Role of Satellite Glial Cells, Astrocytes, and Microglia in Oxaliplatin-Induced Neuropathic Pain." Biomedicines 8, no. 9 (September 2, 2020): 324. http://dx.doi.org/10.3390/biomedicines8090324.

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Oxaliplatin is a third-generation platinum-based chemotherapeutic drug. Although its efficacy against colorectal cancer is well known, peripheral neuropathy that develops during and after infusion of the agents could decrease the quality of life of the patients. Various pathways have been reported to be the cause of the oxaliplatin-induced paresthesia and dysesthesia; however, its mechanism of action has not been fully understood yet. In recent years, researchers have investigated the function of glia in pain, and demonstrated that glia in the peripheral and central nervous system could play a critical role in the development and maintenance of neuropathic pain. These results suggest that targeting the glia may be an effective therapeutic option. In the past ten years, 20 more papers focused on the role of glia in oxaliplatin-induced thermal and mechanical hypersensitivity. However, to date no review has been written to summarize and discuss their results. Thus, in this study, by reviewing 23 studies that conducted in vivo experiments in rodents, the change of satellite glial cells, astrocytes, and microglia activation in the dorsal root ganglia, spinal cord, and the brain of oxaliplatin-induced neuropathic pain animals is discussed.

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Yuasa, Shu, Megumi Kabeya, Satoshi Hibi, Yuko Shirokawa, Chiaki Tokoro, Ryuichi Furuta, Seiji Nagao, Satoshi Kayukawa, Yoshiteru Tanaka, and Kenji Ina. "Retrospective Evaluation of the Analgesic Effects of Molecular Target Agents Against Cancer Pain and Oxaliplatin-Induced Chronic Peripheral Neuropathy." Journal of Analytical Oncology 11 (October 7, 2022): 40–44. http://dx.doi.org/10.30683/1927-7229.2022.11.06.

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Epidermal growth factor receptor (EGFR) has received significant attention for its therapeutic potential for pain relief. The relief of neuropathic pain after treatment with anti-EGFR antibodies or tyrosine kinase inhibitors has been previously described. However, few reports have investigated the association of cancer-related nociceptive pain or chronic chemical induced peripheral neuropathy with the analgesic effects of EGFR inhibition. Therefore, we conducted a retrospective survey of 191 patients with colorectal cancer receiving chemotherapy plus molecular targeting drugs to examine the analgesic effects of anti-EGFR antibodies against either cancer pain or oxaliplatin-induced peripheral neuropathy. We identified a significant difference in the improvement rates of nociceptive pain between panitumumab- and bevacizumab-treated patients (100% vs. 9.1%; p < 0.01), but not oxaliplatin-induced peripheral neuropathy. In conclusion, panitumumab may be effective at reducing cancer-related nociceptive pain.

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Huang, Wan, Jingxiu Huang, Yu Jiang, Xuanwei Huang, Wei Xing, Yaoxuan He, and Handong Ouyang. "Oxaliplatin Regulates Chemotherapy Induced Peripheral Neuropathic Pain in the Dorsal Horn and Dorsal Root Ganglion via the Calcineurin/NFAT Pathway." Anti-Cancer Agents in Medicinal Chemistry 18, no. 8 (December 28, 2018): 1197–207. http://dx.doi.org/10.2174/1871520618666180525091158.

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Objective: The aim of this study was to investigate the mechanism of oxaliplatin in the induction of neuropathic pain as a symptom of Chemotherapy-Induced Peripheral Neuropathy (CIPN). Methods: The CIPN rat model was induced with a one-time injection of oxaliplatin, and the paw withdrawal response was determined using von Frey filaments. The Paw Withdrawal Threshold (PWT) value was recorded and the Dorsal Horn (DH) and Dorsal Root Ganglion (DRG) tissues were collected. The mRNA and protein levels of Calcineurin (CaN), Nuclear Factor of Activated T cells (NFAT), and other relevant cytokines were determined. CaN and NFAT inhibition reagents, FK506 and 11R-VIVIT, were applied in order to investigate the functions of the CaN/NFAT pathway in the neuropathic pain processes. The levels of the downstream inflammatory cytokines, TNF-α and IL-1β, were assessed by ELISA. Results: The application of oxaliplatin reduced the value of PWT by 4 times on days 7（4±1.33）and 14（5.13±3.07）compared with the control group(14±0.91; 13.67±0.76). After treatment, the CaN mRNA level decreased and that of NFAT increased in DH and DRG tissues (P<0.05). However, treatment with FK506 and 11R-VIVIT decreased the value of PWT that had increased after oxaliplatin treatment. The expression of downstream cytokines related to the CaN/NFAT pathway increased, including CCR2, COX2, p-ERK, and p-P38 (all p<0.05). In addition, when the CaN/NFAT pathway was activated, the concentration of TNFα increased to 40pg/mg in DH tissues and 60pg/mg in DRG tissues compared with the control group, while the concentration of IL-1β increased to over 60pg/mg in DH and DRG tissues. Conclusion: It was the first time to prove that oxaliplatin-induced neuropathic pain was correlated to the activation of the CaN/NFAT pathway in our rat model. This finding can provide a new direction to explore the mechanism of oxaliplatin-induced neuropathic pain.

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Zhou, Hai-Hui, Li Zhang, Hai-Xia Zhang, Bo-Rong Xu, Jin-Ping Zhang, Yu-Jie Zhou, Xiao-Ping Qian, and Wei-Hong Ge. "Tat-HA-NR2B9c attenuate oxaliplatin-induced neuropathic pain." Experimental Neurology 311 (January 2019): 80–87. http://dx.doi.org/10.1016/j.expneurol.2018.09.014.

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Egashira, Nobuaki, Shingo Hirakawa, Takehiro Kawashiri, Takahisa Yano, Hiroaki Ikesue, and Ryozo Oishi. "Mexiletine Reverses Oxaliplatin-Induced Neuropathic Pain in Rats." Journal of Pharmacological Sciences 112, no. 4 (2010): 473–76. http://dx.doi.org/10.1254/jphs.10012sc.

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Krøigård, Thomas, Toke K. Svendsen, Martin Wirenfeldt, Henrik D. Schrøder, Camilla Qvortrup, Per Pfeiffer, David Gaist, and Søren H. Sindrup. "Oxaliplatin Neuropathy: Predictive Values of Skin Biopsy, QST and Berve Conduction." Journal of Neuromuscular Diseases 8, no. 4 (July 30, 2021): 679–88. http://dx.doi.org/10.3233/jnd-210630.

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Background: Oxaliplatin-induced peripheral neuropathy negatively affects the quality of life for patients with gastrointestinal cancers and may cause neuropathic pain. Measures of peripheral nerve structure or function, such as intraepidermal nerve fiber density (IENFD) during treatment could reduce neuropathy severity through individualized dose reduction. Objective: The aim was to evaluate the predictive values of IENFD, quantitative sensory testing (QST), and nerve conduction studies (NCS) for significant neuropathy and neuropathic pain. Methods: Fifty-five patients were examined prospectively before, during, and six months following treatment using skin biopsies, QST and NCS. Clinically significant neuropathy six months after treatment was defined as reduced Total Neuropathy Score of more than five and neuropathic pain was assessed according to International Association for the Study of Pain criteria. Results: Thirty patients had a clinically significant neuropathy, and 14 had neuropathic pain. Vibration detection threshold (VDT) before treatment was correlated with clinically significant neuropathy six months after treatment (OR 0.54, p = 0.01) and reductions in cold detection threshold (CDT) after 25% of treatment (OR 1.38, p = 0.04) and heat pain threshold (HPT) after 50% of treatment (OR 1.91, p = 0.03) with neuropathic pain. Cut off values of 5 for baseline VDT and changes of more than –0.05 °C and –0.85 °C in CDT and HPT were estimated. Sensitivity and specificity was low to moderate. There was no correlation between changes in IENFD or NCS and significant neuropathy or neuropathic pain. Conclusions: Vibration detection thresholds and thermal detection thresholds may be useful for prediction of clinically significant and painful neuropathy, respectively. However, low to moderate sensitivity and specificity may limit the predictive value in clinical practice.

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Lee, Ji Hwan, Daeun Min, Donghun Lee, and Woojin Kim. "Zingiber officinale Roscoe Rhizomes Attenuate Oxaliplatin-Induced Neuropathic Pain in Mice." Molecules 26, no. 3 (January 21, 2021): 548. http://dx.doi.org/10.3390/molecules26030548.

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Oxaliplatin is a platinum derivative chemotherapeutic drug widely used against cancers, but even a single treatment can induce a severe allodynia that requires treatment interruption and dose diminution. The rhizome of Zingiber officinale roscoe (Z. officinale, ginger), has been widely used in traditional medicine to treat various diseases causing pain; however, its effect against oxaliplatin-induced neuropathic pain has never been assessed. In mice, a single oxaliplatin (6 mg/kg, i.p.) treatment induced significant cold and mechanical allodynia. Cold and mechanical allodynia were assessed by acetone drop and von Frey filament tests, respectively. Water extracts of Z. officinale (100, 300, and 500 mg/kg, p.o.) significantly attenuated both cold and mechanical allodynia induced by oxaliplatin. Intrathecal pre-treatment with the antagonist 5-HT1A (NAN-190, i.t., 1 μg), but not with the antagonist 5-HT2A (ketanserin, i.t., 1 μg), significantly blocked the analgesic effect of Z. officinale against both cold and mechanical allodynia. However, 5-HT3 antagonist (MDL-72222, i.t., 15 μg) administration only blocked the anti-allodynic effect of Z. officinale against cold allodynia. Real-time PCR analysis demonstrated that Z. officinale significantly increased the mRNA expression of the spinal 5-HT1A receptor that was downregulated after oxaliplatin injection. These results suggest that Z. officinale may be a viable treatment option for oxaliplatin-induced neuropathic pain.

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Sałat, Kinga, Anna Furgała-Wojas, and Robert Sałat. "The Microglial Activation Inhibitor Minocycline, Used Alone and in Combination with Duloxetine, Attenuates Pain Caused by Oxaliplatin in Mice." Molecules 26, no. 12 (June 11, 2021): 3577. http://dx.doi.org/10.3390/molecules26123577.

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The antitumor drug, oxaliplatin, induces neuropathic pain, which is resistant to available analgesics, and novel mechanism-based therapies are being evaluated for this debilitating condition. Since activated microglia, impaired serotonergic and noradrenergic neurotransmission and overexpressed sodium channels are implicated in oxaliplatin-induced pain, this in vivo study assessed the effect of minocycline, a microglial activation inhibitor used alone or in combination with ambroxol, a sodium channel blocker, or duloxetine, a serotonin and noradrenaline reuptake inhibitor, on oxaliplatin-induced tactile allodynia and cold hyperalgesia. To induce neuropathic pain, a single dose (10 mg/kg) of intraperitoneal oxaliplatin was used. The mechanical and cold pain thresholds were assessed using mouse von Frey and cold plate tests, respectively. On the day of oxaliplatin administration, only duloxetine (30 mg/kg) and minocycline (100 mg/kg) used alone attenuated both tactile allodynia and cold hyperalgesia 1 h and 6 h after administration. Minocycline (50 mg/kg), duloxetine (10 mg/kg) and combined minocycline + duloxetine influenced only tactile allodynia. Seven days after oxaliplatin, tactile allodynia (but not cold hyperalgesia) was attenuated by minocycline (100 mg/kg), duloxetine (30 mg/kg) and combined minocycline and duloxetine. These results indicate a potential usefulness of minocycline used alone or combination with duloxetine in the treatment of oxaliplatin-induced pain.

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Tian, Liujun, Tianren Fan, Nan Zhou, Hui Guo, and Weijie Zhang. "Role of PAR2 in regulating oxaliplatin-induced neuropathic pain via TRPA1." Translational Neuroscience 6, no. 1 (January 1, 2015): 111–16. http://dx.doi.org/10.1515/tnsci-2015-0010.

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AbstractOxaliplatin (OXL) is a third-generation chemotherapeutic agent commonly used to treat metastatic digestive tumors; however, one of the main limiting complications of OXL is neuropathic pain. In this study, the underlying mechanisms responsible for OXL evoked-neuropathic pain were examined. Using a rat model, the results demonstrated that intraperitoneal (i.p.) injection of OXL significantly increased mechanical pain and cold sensitivity as compared with control animals (P < 0.05 vs. control rats). Blocking proteinase-activated receptor 2 (PAR2) significantly attenuated mechanical pain and cold sensitivity observed in control rats and OXL rats (P < 0.05 vs. vehicle control). The attenuating effect of PAR2 on mechanical pain and cold sensitivity were significantly smaller in OXL-rats than in control rats. The role played by PAR2 downstream signaling pathways [namely, transient receptor potential ankyrin 1 (TRPA1)] in regulating OXL evoked-neuropathic pain was also examined. The data shows that TRPA1 expression was upregulated in the lumbar dorsal root ganglion (DRG) of OXL rats and blocking TRPA1 inhibited mechanical pain and heightened cold sensitivity (P <0.05 vs. control rats). Blocking PAR2 also significantly decreased TRPA1expression in the DRG. Findings in this study show that OXL intervention amplifies mechanical hyperalgesia and cold hypersensitivity and PAR2 plays an important role in regulating OXLinduced neuropathic pain via TRPA1 pathways.

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Karthaus, M., C. S. Karapetis, M. Brown, N. Pavlakis, T. Trarbach, N. Marschner, H. A. Duerk, and L. Manzione. "A randomized, double-blind, placebo-controlled trial for prevention of oxaliplatin-induced neuropathy symptoms with pregabalin." Journal of Clinical Oncology 29, no. 4_suppl (February 1, 2011): 553. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.553.

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553 Background: Sensorial peripheral neuropathy (PNP) is a major limitation for pts receiving oxaliplatin-based ctx for CRC. Pregabalin is widely used for treatment of oxaliplatin-induced PNP. We evaluated the efficacy of pregabalin vs. placebo for the prevention of paresthesia from the onset of oxaliplatin-based ctx over each cycle. Methods: Rd, db, placebo-controlled study in adult CRC pts with ECOG 0-2 to undergo a new oxaliplatin/5-FU/FA-based ctx. Pts were excluded if they had neuropathic pain or other of painful paresthesia prior to baseline. Paresthesia, dysesthesia, and pain were rated on a numerical scale (NRS 0-10) every day. Primary endpoint was the time of onset of persistent symptoms (NRS >4). Results: Of the 69 screened pts, 64 were randomized and 61 received study medication (32 pregabalin vs. 29 placebo). Pts were balanced in both arms regarding age, sex, stage, and ctx. There were no differences between both treatment groups for all PNP parameters at any cycle. One pt in both arms developed paresthesia (5.3%) after 9 cycles of ctx, 1 pt had persistent pain (placebo arm). During the follow-up period persistent paresthesic, dysesthesic, and persistent pain developed in 2 vs. 1, 2 vs. 2, and 0 vs. 2 pts, respectively. The study was terminated after a blinded data review found that there were very few events of persistent symptoms, which was then confirmed an interim analysis. Nausea and anorexia were the most frequently reported AE in both groups. Conclusions: The results of this study, which was terminated early at interim analysis, is that too few patients developed persistent symptoms to allow any meaningful treatment difference for prevention of neuropathic pain related to oxaliplatin by pregabalin. There remains an unmet need for oxaliplatin-induced PNP with new trial design issues in this field urgently needed. No significant financial relationships to disclose.

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Chae, Hyeon Kyeong, Woojin Kim, and Sun Kwang Kim. "Phytochemicals of Cinnamomi Cortex: Cinnamic Acid, but not Cinnamaldehyde, Attenuates Oxaliplatin-Induced Cold and Mechanical Hypersensitivity in Rats." Nutrients 11, no. 2 (February 19, 2019): 432. http://dx.doi.org/10.3390/nu11020432.

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A chemotherapy drug, oxaliplatin, induces cold and mechanical hypersensitivity, but effective treatments for this neuropathic pain without side effects are still lacking. We previously showed that Cinnamomi Cortex suppresses oxaliplatin-induced pain behaviors in rats. However, it remains unknown which phytochemical of Cinnamomi Cortex plays a key role in that analgesic action. Thus, here we investigated whether and how cinnamic acid or cinnamaldehyde, major components of Cinnamomi Cortex, alleviates cold and mechanical allodynia induced by a single oxaliplatin injection (6 mg/kg, i.p.) in rats. Using an acetone test and the von Frey test for measuring cold and mechanical allodynia, respectively, we found that administration of cinnamic acid, but not cinnamaldehyde, at doses of 10, 20 and 40 mg/kg (i.p.) significantly attenuates the allodynic behaviors in oxaliplatin-injected rats with the strongest effect being observed at 20 mg/kg. Our in vivo extracellular recordings also showed that cinnamic acid (20 mg/kg, i.p.) inhibits the increased activities of spinal wide dynamic range neurons in response to cutaneous mechanical and cold stimuli following the oxaliplatin injection. These results indicate that cinnamic acid has an effective analgesic action against oxaliplatin-induced neuropathic pain through inhibiting spinal pain transmission, suggesting its crucial role in mediating the effect of Cinnamomi Cortex.

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Deng, Bo, Liqun Jia, Lin Pan, Aiping Song, Yuanyuan Wang, Huangying Tan, Qing Xiang, Lili Yu, and Dandan Ke. "Wen-Luo-Tong Prevents Glial Activation and Nociceptive Sensitization in a Rat Model of Oxaliplatin-Induced Neuropathic Pain." Evidence-Based Complementary and Alternative Medicine 2016 (2016): 1–7. http://dx.doi.org/10.1155/2016/3629489.

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One of the main dose-limiting complications of the chemotherapeutic agent oxaliplatin (OXL) is painful neuropathy. Glial activation and nociceptive sensitization may be responsible for the mechanism of neuropathic pain. The Traditional Chinese Medicine (TCM) Wen-luo-tong (WLT) has been widely used in China to treat chemotherapy induced neuropathic pain. However, there is no study on the effects of WLT on spinal glial activation induced by OXL. In this study, a rat model of OXL-induced chronic neuropathic pain was established and WLT was administrated. Pain behavioral tests and morphometric examination of dorsal root ganglia (DRG) were conducted. Glial fibrillary acidic protein (GFAP) immunostaining was performed, glial activation was evaluated, and the excitatory neurotransmitter substance P (SP) and glial-derived proinflammatory cytokine tumor necrosis factor-α(TNF-α) were analyzed. WLT treatment alleviated OXL-induced mechanical allodynia and mechanical hyperalgesia. Changes in the somatic, nuclear, and nucleolar areas of neurons in DRG were prevented. In the spinal dorsal horn, hypertrophy and activation of GFAP-positive astrocytes were averted, and the level of GFAP mRNA decreased significantly. Additionally, TNF-αmRNA and protein levels decreased. Collectively, these results indicate that WLT reversed both glial activation in the spinal dorsal horn and nociceptive sensitization during OXL-induced chronic neuropathic pain in rats.

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FUJIMURA, Takeshi, Aiko IGUCHI, Atsushi SATO, Shinji KAGAYA, Tatsuo HOSHINO, and Takashi TAKEUCHI. "The pain-relieving effects of lactoferrin on oxaliplatin-induced neuropathic pain." Journal of Veterinary Medical Science 82, no. 11 (2020): 1648–54. http://dx.doi.org/10.1292/jvms.20-0034.

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Liu, Yun, Guangquan Zhou, and Nenggui Xu. "Effect of Metformin Nanoparticle-Mediated Thioredoxin Interacting Protein Expression on Oxaliplatin-Induced Peripheral Neuralgia." Journal of Nanoscience and Nanotechnology 20, no. 10 (October 1, 2020): 6123–32. http://dx.doi.org/10.1166/jnn.2020.18508.

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Oxaliplatin (LOHP) is an approved anti-cancer drug that often accumulates in the peripheral nerves during the treatment of cancer. Metformin is a prescription drug with a wide range of pharmacological effects, which can augment the anti-cancer efficacy of chemotherapy drugs. Recent studies suggest that metformin is a potential drug that can relieve oxaliplatin induced neuralgia, and autophagy plays an important role in it. This study aims at exploring the effect and mechanism of action of metformin on oxaliplatin-induced peripheral neuropathic pain. To explore the underlying mechanism of metformin on peripheral nerves, neuropathic pain model was developed by intraperitoneal injection of oxaliplatin into mice. Metformin nanoparticles encapsulated by PLGA were used to intervene the pain in the model mice. RT-qPCR and immunoblotting were used to detect the effects of metformin on the expression of TXNIP and autophagy associated genes-BECN1 and LC3B in the sciatic nerves of pain model mice. Hematoxylin and eosin staining were used to detect the pathological changes in the sciatic nerve. Flow cytometry and Annexin V-FITC/PI apoptosis detection kit were used to detect the apoptosis of sciatic nerve cells. The effect of metformin on the pain perception of mice was detected by thermal and mechanical stimulation experiments. The results showed that the expression of TXNIP and autophagy related indexes-BECN1 and LC3B in sciatic nerve decreased significantly after oxaliplatin treatment. However, metformin intervention resulted in significant up-regulation of TXNIP and autophagy related indexes, and augmented the threshold of thermal sensitivity and mechanical tingling. Thus, our study has identified TXNIP as a novel target for oxaliplatin induced peripheral nerve pain. We have shown that oxaliplatin inhibits TXNIP expression, regulates autophagy, thereby affecting neuralgia. In contrast, metformin promotes the expression of TXNIP and autophagy of cells thereby inhibiting neural sensitivity and thus results in pain relief.

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Huynh, Peter N., Denise Giuvelis, Sean Christensen, Kerry L. Tucker, and J. Michael McIntosh. "RgIA4 Accelerates Recovery from Paclitaxel-Induced Neuropathic Pain in Rats." Marine Drugs 18, no. 1 (December 21, 2019): 12. http://dx.doi.org/10.3390/md18010012.

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Chemotherapeutic drugs are widely utilized in the treatment of human cancers. Painful chemotherapy-induced neuropathy is a common, debilitating, and dose-limiting side effect for which there is currently no effective treatment. Previous studies have demonstrated the potential utility of peptides from the marine snail from the genus Conus for the treatment of neuropathic pain. α-Conotoxin RgIA and a potent analog, RgIA4, have previously been shown to prevent the development of neuropathy resulting from the administration of oxaliplatin, a platinum-based antineoplastic drug. Here, we have examined its efficacy against paclitaxel, a chemotherapeutic drug that works by a mechanism of action distinct from that of oxaliplatin. Paclitaxel was administered at 2 mg/kg (intraperitoneally (IP)) every other day for a total of 8 mg/kg. Sprague Dawley rats that were co-administered RgIA4 at 80 µg/kg (subcutaneously (SC)) once daily, five times per week, for three weeks showed significant recovery from mechanical allodynia by day 31. Notably, the therapeutic effects reached significance 12 days after the last administration of RgIA4, which is suggestive of a rescue mechanism. These findings support the effects of RgIA4 in multiple chemotherapeutic models and the investigation of α9α10 nicotinic acetylcholine receptors (nAChRs) as a non-opioid target in the treatment of chronic pain.

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Huynh, Peter N., Sean B. Christensen, and J. Michael McIntosh. "RgIA4 Prevention of Acute Oxaliplatin-Induced Cold Allodynia Requires α9-Containing Nicotinic Acetylcholine Receptors and CD3+ T-Cells." Cells 11, no. 22 (November 11, 2022): 3561. http://dx.doi.org/10.3390/cells11223561.

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Chemotherapy-induced neuropathic pain is a debilitating and dose-limiting side effect. Oxaliplatin is a third-generation platinum and antineoplastic compound that is commonly used to treat colorectal cancer and commonly yields neuropathic side effects. Available drugs such as duloxetine provide only modest benefits against oxaliplatin-induced neuropathy. A particularly disruptive symptom of oxaliplatin is painful cold sensitivity, known as cold allodynia. Previous studies of the Conus regius peptide, RgIA, and its analogs have demonstrated relief from oxaliplatin-induced cold allodynia, yielding improvement that persists even after treatment cessation. Moreover, underlying inflammatory and neuronal protection were shown at the cellular level in chronic constriction nerve injury models, consistent with disease-modifying effects. Despite these promising preclinical outcomes, the underlying molecular mechanism of action of RgIA4 remains an area of active investigation. This study aimed to determine the necessity of the α9 nAChR subunit and potential T-cell mechanisms in RgIA4 efficacy against acute oxaliplatin-induced cold allodynia. A single dose of oxaliplatin (10 mg/kg) was utilized followed by four daily doses of RgIA4. Subcutaneous administration of RgIA4 (40 µg/kg) prevented cold allodynia in wildtype mice but not in mice lacking the α9 nAChR-encoding gene, chrna9. RgIA4 also failed to reverse allodynia in mice depleted of CD3+ T-cells. In wildtype mice treated with oxaliplatin, quantitated circulating T-cells remained unaffected by RgIA4. Together, these results show that RgIA4 requires both chrna9 and CD3+ T-cells to exert its protective effects against acute cold-allodynia produced by oxaliplatin.

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Lee, Ji Hwan, Juan Gang, Eunhee Yang, Woojin Kim, and Young-Ho Jin. "Bee Venom Acupuncture Attenuates Oxaliplatin-Induced Neuropathic Pain by Modulating Action Potential Threshold in A-Fiber Dorsal Root Ganglia Neurons." Toxins 12, no. 12 (November 24, 2020): 737. http://dx.doi.org/10.3390/toxins12120737.

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Oxaliplatin is a third-generation platinum-based chemotherapeutic drug widely used in colorectal cancer treatment. Although potent against this tumor, it can induce cold and mechanical allodynia even after a single injection. The currently used drugs to attenuate this allodynia can also cause unwanted effects, which limit their use. Bee venom acupuncture (BVA) is widely used in Korean medicine to treat pain. Although the effect of BVA on oxaliplatin-induced neuropathic pain has been addressed in many studies, its action on dorsal root ganglia (DRG) neurons has never been investigated. A single oxaliplatin injection (6 mg/kg, intraperitoneally) induced cold and mechanical allodynia, and BVA (0.1 and 1 mg/kg, subcutaneous, ST36) dose-dependently decreased allodynia in rats. On acutely dissociated lumbar 4–6 DRG neurons, 10 min application of oxaliplatin (100 μM) shifted the voltage-dependence of sodium conductance toward negative membrane potentials in A- but not C-fibers. The resting membrane potential remained unchanged, but the action potential threshold decreased significantly compared to that of the control (p < 0.05). However, 0.1 μg/mL of BVA administration increased the lowered action potential threshold. In conclusion, these results suggest that BVA may attenuate oxaliplatin-induced neuropathic pain by altering the action potential threshold in A-fiber DRG neurons.

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Huang, Zhen-Zhen, Dai Li, Han-Dong Ou-Yang, Cui-Cui Liu, Xian-Guo Liu, Chao Ma, Jia-You Wei, Yong Liu, and Wen-Jun Xin. "Cerebrospinal Fluid Oxaliplatin Contributes to the Acute Pain Induced by Systemic Administration of Oxaliplatin." Anesthesiology 124, no. 5 (May 1, 2016): 1109–21. http://dx.doi.org/10.1097/aln.0000000000001084.

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Abstract Background Systemic administration of oxaliplatin has no effect on the tumors in the central nervous system (CNS) due to the limited concentration of oxaliplatin in the cerebrospinal fluid (CSF), while it was clinically reported that oxaliplatin can induce acute encephalopathy. Currently, the impairment of neuronal functions in the CNS after systemic administration of oxaliplatin remains uninvestigated. Methods The von Frey test and the plantar test were performed to evaluate neuropathic pain behavior after a single intraperitoneal administration of oxaliplatin (4 mg/kg) in rats. Inductively coupled plasma–mass spectrometry, electrophysiologic recording, real-time quantitative reverse transcription polymerase chain reaction, chromatin immunoprecipitation, Western blot, immunohistochemistry, and small interfering RNA were applied to understand the mechanisms. Results Concentration of oxaliplatin in CSF showed a time-dependent increase after a single administration of oxaliplatin. Spinal application of oxaliplatin at the detected concentration (6.6 nM) significantly increased the field potentials in the dorsal horn, induced acute mechanical allodynia (n = 12 each) and thermal hyperalgesia (n = 12 each), and enhanced the evoked excitatory postsynaptic currents and spontaneous excitatory postsynaptic currents in the projection neurokinin 1 receptor–expressing lamina I to II neurons. The authors further found that oxaliplatin significantly increased the nuclear factor-κB p65 binding and histone H4 acetylation in cx3cl1 promoter region. Thus, the upregulated spinal CX3CL1 markedly mediated the induction of central sensitization and acute pain behavior after oxaliplatin administration. Conclusions The findings of this study suggested that oxaliplatin in CSF may directly impair the normal function of central neurons and contribute to the rapid development of CNS-related side effects during chemotherapy. This provides novel targets to prevent oxaliplatin-induced acute painful neuropathy and encephalopathy.

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Rimola, Vittoria, Tabea Osthues, Vanessa Königs, Gerd Geißlinger, and Marco Sisignano. "Oxaliplatin Causes Transient Changes in TRPM8 Channel Activity." International Journal of Molecular Sciences 22, no. 9 (May 7, 2021): 4962. http://dx.doi.org/10.3390/ijms22094962.

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Oxaliplatin is a third-generation platinum-based anticancer drug that is widely used as first-line treatment for colorectal carcinoma. Patients treated with oxaliplatin develop an acute peripheral pain several hours after treatment, mostly characterized by cold allodynia as well as a long-term chronic neuropathy. These two phenomena seem to be causally connected. However, the underlying mechanisms that trigger the acute peripheral pain are still poorly understood. Here we show that the activity of the transient receptor potential melastatin 8 (TRPM8) channel but not the activity of any other member of the TRP channel family is transiently increased 1 h after oxaliplatin treatment and decreased 24 h after oxaliplatin treatment. Mechanistically, this is connected with activation of the phospholipase C (PLC) pathway and depletion of phosphatidylinositol 4,5-bisphosphate (PIP2) after oxaliplatin treatment. Inhibition of the PLC pathway can reverse the decreased TRPM8 activity as well as the decreased PIP2-concentrations after oxaliplatin treatment. In summary, these results point out transient changes in TRPM8 activity early after oxaliplatin treatment and a later occurring TRPM8 channel desensitization in primary sensory neurons. These mechanisms may explain the transient cold allodynia after oxaliplatin treatment and highlight an important role of TRPM8 in oxaliplatin-induced acute and neuropathic pain.

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Mokhtar, Nazarine, Marcin Drop, Florian Jacquot, Sylvain Lamoine, Eric Chapuy, Laetitia Prival, Youssef Aissouni, et al. "The Constitutive Activity of Spinal 5-HT6 Receptors Contributes to Diabetic Neuropathic Pain in Rats." Biomolecules 13, no. 2 (February 15, 2023): 364. http://dx.doi.org/10.3390/biom13020364.

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Diabetic neuropathy is often associated with chronic pain. Serotonin type 6 (5-HT6) receptor ligands, particularly inverse agonists, have strong analgesic potential and may be new candidates for treating diabetic neuropathic pain and associated co-morbid cognitive deficits. The current study addressed the involvement of 5-HT6 receptor constitutive activity and mTOR signaling in an experimental model of diabetic neuropathic pain induced by streptozocin (STZ) injection in the rat. Here, we show that mechanical hyperalgesia and associated cognitive deficits are suppressed by the administration of 5-HT6 receptor inverse agonists or rapamycin. The 5-HT6 receptor ligands also reduced tactile allodynia in traumatic and toxic neuropathic pain induced by spinal nerve ligation and oxaliplatin injection. Furthermore, both painful and co-morbid cognitive symptoms in diabetic rats are reduced by intrathecal delivery of a cell-penetrating peptide that disrupts 5-HT6 receptor-mTOR physical interaction. These findings demonstrate the deleterious influence of the constitutive activity of spinal 5-HT6 receptors upon painful and cognitive symptoms in diabetic neuropathic pains of different etiologies. They suggest that targeting the constitutive activity of 5-HT6 receptors with inverse agonists or disrupting the 5-HT6 receptor-mTOR interaction might be valuable strategies for the alleviation of diabetic neuropathic pain and cognitive co-morbidities.

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Furgała-Wojas, Anna, Magdalena Kowalska, Alicja Nowaczyk, Łukasz Fijałkowski, and Kinga Sałat. "Comparison of Bromhexine and its Active Metabolite - Ambroxol as Potential Analgesics Reducing Oxaliplatin-induced Neuropathic Pain - Pharmacodynamic and Molecular Docking Studies." Current Drug Metabolism 21, no. 7 (November 5, 2020): 548–61. http://dx.doi.org/10.2174/1389200221666200711155632.

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Background: Painful peripheral neuropathy is a dose-limiting adverse effect of the antitumor drug oxaliplatin. The main symptoms of neuropathy: tactile allodynia and cold hyperalgesia, appear in more than 80% of patients on oxaliplatin therapy and are due to the overexpression of neuronal sodium channels (Navs) and neuroinflammation. Objective: This study assessed antiallodynic and antihyperalgesic properties of two repurposed drugs with antiinflammatory and Nav-blocking properties (bromhexine and its pharmacologically active metabolite - ambroxol) in a mouse model of neuropathic pain induced by oxaliplatin. Using molecular docking techniques, we predicted targets implicated in the observed in vivo activity of bromhexine. Methods: Oxaliplatin (a single intraperitoneal dose of 10 mg/kg) induced tactile allodynia and cold hyperalgesia in CD-1 mice and the effectiveness of single-dose or repeated-dose bromhexine and ambroxol to attenuate pain hypersensitivity was assessed in von Frey and cold plate tests. Additionally, Veber analysis and molecular docking experiments of bromhexine on mouse (m) and human (h) Nav1.6-1.9 were carried out. Results: At the corresponding doses, ambroxol was more effective than bromhexine as an antiallodynic agent. However, at the dose of 150 mg/kg, ambroxol induced motor impairments in mice. Repeated-dose bromhexine and ambroxol partially attenuated the development of late-phase tactile allodynia in oxaliplatin-treated mice. Only 7-day administration of bromhexine attenuated the development of late-phase cold hyperalgesia. Bromhexine was predicted to be a strong inhibitor of mNav1.6, mNav1.7, mNav1.9, and hNav1.7-hNav1.9. Conclusion: The conversion of bromhexine to other than ambroxol active metabolites should be considered when interpreting some of its in vivo effects. Nav-blocking properties of bromhexine (and previously also predicted for ambroxol) might underlie its ability to attenuate pain caused by oxaliplatin.

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Cuzzocrea, Salvatore, Marika Lanza, Michela Campolo, Giovanna Casili, Irene Paterniti, Alessia Filippone, and Emanuela Esposito. "Neuroprotective effect of PEA‐OXA on oxaliplatin‐Induced neuropathic pain." FASEB Journal 34, S1 (April 2020): 1. http://dx.doi.org/10.1096/fasebj.2020.34.s1.03994.

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Kerckhove, Nicolas, Jérome Busserolles, Trevor Stanbury, Bruno Pereira, Valérie Plence, Franck Bonnetain, Ivan Krakowski, Alain Eschalier, Denis Pezet, and David Balayssac. "Effectiveness assessment of riluzole in the prevention of oxaliplatin-induced peripheral neuropathy: RILUZOX-01: protocol of a randomised, parallel, controlled, double-blind and multicentre study by the UNICANCER-AFSOS Supportive Care intergroup." BMJ Open 9, no. 6 (June 2019): e027770. http://dx.doi.org/10.1136/bmjopen-2018-027770.

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IntroductionMost patients (>70%) experience acute neuropathic symptoms shortly after oxaliplatin infusions. These symptoms are not always resolved between infusions. Overall, 30%–50% of patients suffer from chronic oxaliplatin-induced peripheral neuropathy (OIPN). This cumulative and dose-dependent sensory neuropathy limits compliance or results in oxaliplatin-based chemotherapies to be substituted with less neurotoxic agents. These treatment changes impair clinical outcomes, and may be associated with comorbidities, such as distress, depression and anxiety. Currently, no drug used to prevent or treat OIPN is sufficiently effective to be used routinely in clinical practice. There is, thus, an unmet therapeutic need to reduce the intensity of and/or prevent OIPN. We hypothesised that riluzole would be an excellent candidate to address this public health issue. Riluzole is approved for treating amyotrophic lateral sclerosis. In animals, there is a beneficial effect on sensorimotor and pain disorders, as well as related comorbidities, after repeated administration of oxaliplatin. In humans, riluzole has shown neuroprotective, anxiolytic and antidepressive effects.Methods and analysisRILUZOX-01 trial was designed as a randomised, controlled, double-blind study to evaluate the efficacy of riluzole to prevent OIPN. Patients with colorectal cancer and initiating adjuvant oxaliplatin-based chemotherapy are eligible. Patients (n=210) will be randomly assigned to either riluzole or placebo, concomitantly with chemotherapy. The primary endpoint is the change in OIPN intensity, assessed by the sensory scale of the QLQ-CIPN20, after six 2-week cycles of chemotherapy. Secondary endpoints include incidence and severity of neuropathy, grade of sensory neuropathy, intensity and features of neuropathic pain, health-related quality of life, disease-free survival, overall survival and safety.Ethics and dessiminationThe study was approved by a French ethics committee (ref:39/18_1, ‘Comité de Protection des Personnes’ Ouest-IV, France) and plans to start enroling patients in September 2019. The trial is registered in EudraCT and clinicaltrials.gov.Trial registration numberN°2017-002320-25;NCT03722680

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Cinci, Lorenzo, Lorenzo Di Cesare Mannelli, Anna Maidecchi, Luisa Mattoli, and Carla Ghelardini. "Effects of Hypericum perforatum extract on oxaliplatin-induced neurotoxicity: in vitro evaluations." Zeitschrift für Naturforschung C 72, no. 5-6 (May 1, 2017): 219–26. http://dx.doi.org/10.1515/znc-2016-0194.

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Abstract Hypericum perforatum L. has been used for centuries as a natural remedy for the treatment of many disorders. Neuropathic pain is a common side effect of oxaliplatin-based chemotherapy and often the cause of therapy discontinuation. Thanks to its anti-inflammatory and analgesic effects, the use of H. perforatum may be a novel therapeutic strategy for neuropathy. The aim of this paper was to evaluate the effect of H. perforatum hydrophilic extract on an in vitro model of oxaliplatin-induced neurotoxicity. The antioxidant potential of extract was first evaluated in cell-free models by the thiobarbituric acid-reactive substances assay and nitro blue tetrazolium oxidation test; the ability of H. perforatum extract to reduce oxaliplatin-induced caspase-3 activity in rat astrocytes and its potential interference with the cytotoxic effects of oxaliplatin in a colorectal cancer in vitro model (HT-29 cells) were also evaluated. The extract showed a significant antioxidant effect and was able to reduce caspase-3 activity in rat astrocytes. Of note, the extract alone exerted a cytotoxic effect in HT-29 cells and did not reduce the cytotoxicity of oxaliplatin in HT-29 cells. These data suggest that H. perforatum could be used as a novel therapeutic strategy for counteracting chemotherapy-induced neuropathy.

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MacDonald, Donald Iain, Ana P. Luiz, Federico Iseppon, Queensta Millet, Edward C. Emery, and John N. Wood. "Silent cold-sensing neurons contribute to cold allodynia in neuropathic pain." Brain 144, no. 6 (March 9, 2021): 1711–26. http://dx.doi.org/10.1093/brain/awab086.

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Abstract Patients with neuropathic pain often experience innocuous cooling as excruciating pain. The cell and molecular basis of this cold allodynia is little understood. We used in vivo calcium imaging of sensory ganglia to investigate how the activity of peripheral cold-sensing neurons was altered in three mouse models of neuropathic pain: oxaliplatin-induced neuropathy, partial sciatic nerve ligation, and ciguatera poisoning. In control mice, cold-sensing neurons were few in number and small in size. In neuropathic animals with cold allodynia, a set of normally silent large diameter neurons became sensitive to cooling. Many of these silent cold-sensing neurons responded to noxious mechanical stimuli and expressed the nociceptor markers Nav1.8 and CGRPα. Ablating neurons expressing Nav1.8 resulted in diminished cold allodynia. The silent cold-sensing neurons could also be activated by cooling in control mice through blockade of Kv1 voltage-gated potassium channels. Thus, silent cold-sensing neurons are unmasked in diverse neuropathic pain states and cold allodynia results from peripheral sensitization caused by altered nociceptor excitability.

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Ahn, Byung-Soo, Seong-Kyu Kim, Ha Neul Kim, Ji-Hye Lee, Ji-Hwan Lee, Deog Sang Hwang, Hyunsu Bae, Byung-Il Min, and Sun Kwang Kim. "Gyejigachulbu-Tang Relieves Oxaliplatin-Induced Neuropathic Cold and Mechanical Hypersensitivity in Rats via the Suppression of Spinal Glial Activation." Evidence-Based Complementary and Alternative Medicine 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/436482.

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Activation of spinal glial cells plays a crucial role in the pathogenesis of neuropathic pain. An administration of oxaliplatin, an important anticancer drug, often induces acute neuropathic cold hypersensitivity and/or mechanical hypersensitivity in patients. Gyejigachulbu-tang (GBT), a herbal formula comprisingCinnamomi Cortex, Paeoniae Radix, Atractylodis Lanceae Rhizoma, Zizyphi Fructus, Glycyrrhizae Radix, Zingiberis Rhizoma,andAconiti Tuber, has been used in East Asia to treat various pain symptoms, especially in cold patients. This study investigated whether and how GBT alleviates oxaliplatin-induced cold and mechanical hypersensitivity in rats. The behavioral signs of cold and mechanical hypersensitivity were evaluated by a tail immersion test in cold water (4°C) and a von Frey hair test, respectively. The significant cold and mechanical hypersensitivity were observed 3 days after an oxaliplatin injection (6 mg/kg, i.p.). Daily oral administration of GBT (200, 400, and 600 mg/kg) for 5 days markedly attenuated cold and mechanical hypersensitivity. Immunoreactivities of glial fibrillary acidic protein (GFAP, astrocyte marker) and OX-42 (microglia marker) in the spinal dorsal horn were significantly increased by an oxaliplatin injection, which were restored by GBT administration. These results indicate that GBT relieves oxaliplatin-induced cold and mechanical hypersensitivity in rats possibly through the suppression of spinal glial activation.

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Lee, Ji Hwan, Jong Hee Choi, Jaihwan Kim, Tai Wan Kim, Ji-Young Kim, Geehoon Chung, Ik-Hyun Cho, Dae Sik Jang, and Sun Kwang Kim. "Syringaresinol Alleviates Oxaliplatin-Induced Neuropathic Pain Symptoms by Inhibiting the Inflammatory Responses of Spinal Microglia." Molecules 27, no. 23 (November 23, 2022): 8138. http://dx.doi.org/10.3390/molecules27238138.

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Oxaliplatin-induced peripheral neuropathy (OIPN) is a serious side effect that impairs the quality of life of patients treated with the chemotherapeutic agent, oxaliplatin. The underlying pathophysiology of OIPN remains unclear, and there are no effective therapeutics. This study aimed to investigate the causal relationship between spinal microglial activation and OIPN and explore the analgesic effects of syringaresinol, a phytochemical from the bark of Cinnamomum cassia, on OIPN symptoms. The causality between microglial activation and OIPN was investigated by assessing cold and mechanical allodynia in mice after intrathecal injection of the serum supernatant from a BV-2 microglial cell line treated with oxaliplatin. The microglial inflammatory response was measured based on inducible nitric oxide synthase (iNOS), phosphorylated extracellular signal-regulated kinase (p-ERK), and phosphorylated nuclear factor-kappa B (p-NF-κB) expression in the spinal dorsal horn. The effects of syringaresinol were tested using behavioral and immunohistochemical assays. We found that oxaliplatin treatment activated the microglia to increase inflammatory responses, leading to the induction of pain. Syringaresinol treatment significantly ameliorated oxaliplatin-induced pain and suppressed microglial expression of inflammatory signaling molecules. Thus, we concluded that the analgesic effects of syringaresinol on OIPN were achieved via the modulation of spinal microglial inflammatory responses.

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Lim, Bong-Soo, Hak Jin Moon, Dong Xing Li, Munsoo Gil, Joon Ki Min, Giseog Lee, Hyunsu Bae, Sun Kwang Kim, and Byung-Il Min. "Effect of Bee Venom Acupuncture on Oxaliplatin-Induced Cold Allodynia in Rats." Evidence-Based Complementary and Alternative Medicine 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/369324.

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Oxaliplatin, a chemotherapy drug, often leads to neuropathic cold allodynia after a single administration. Bee venom acupuncture (BVA) has been used in Korea to relieve various pain symptoms and is shown to have a potent antiallodynic effect in nerve-injured rats. We examined whether BVA relieves oxaliplatin-induced cold allodynia and which endogenous analgesic system is implicated. The cold allodynia induced by an oxaliplatin injection (6 mg/kg, i.p.) was evaluated by immersing the rat’s tail into cold water (4°C) and measuring the withdrawal latency. BVA (1.0 mg/kg, s.c.) at Yaoyangguan (GV3), Quchi (LI11), or Zusanli (ST36) acupoints significantly reduced cold allodynia with the longest effect being shown in the GV3 group. Conversely, a high dose of BVA (2.5 mg/kg) at GV3 did not show a significant antiallodynic effect. Phentolamine (α-adrenergic antagonist, 2 mg/kg, i.p.) partially blocked the relieving effect of BVA on allodynia, whereas naloxone (opioid antagonist, 2 mg/kg, i.p.) did not. We further confirmed that an intrathecal administration of idazoxan (α2-adrenergic antagonist, 50 μg) blocked the BVA-induced anti-allodynic effect. These results indicate that BVA alleviates oxaliplatin-induced cold allodynia in rats, at least partly, through activation of the noradrenergic system. Thus, BVA might be a potential therapeutic option in oxaliplatin-induced neuropathy.

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Yu, Wenli, Zhenli Zheng, Wei Wei, Lei Li, Yidan Zhang, Yanyan Sun, Jing Cao, Weidong Zang, and Jinping Shao. "Raf1 interacts with OIP5 to participate in oxaliplatin-induced neuropathic pain." Life Sciences 281 (September 2021): 119804. http://dx.doi.org/10.1016/j.lfs.2021.119804.

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Bennedsgaard, K. J., L. Ventzel, A. B. Jensen, A. R. Jensen, H. Tankisi, and N. B. Finnerup. "Chronic neuropathic pain following oxaliplatin and docetaxel: A 5-year follow-up questionnaire study." Scandinavian Journal of Pain 16, no. 1 (July 1, 2017): 166. http://dx.doi.org/10.1016/j.sjpain.2017.04.009.

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AbstractBackgroundAdjuvant chemotherapy with docetaxel and oxaliplatin increases survival in patients with high-risk breast and colorectal cancer, respectively, but may induce acute and chronic neurotoxicity. This study is a 5-year follow-up of chronic chemotherapy-induced peripheral neuropathy (CIPN).MethodsIn 2011–2012, 74 patients with high-risk colorectal cancer and 100 patients with high-risk breast cancer answered a questionnaire before, during and one year after receiving adjuvant chemotherapy with oxaliplatin and docetaxel, respectively. In 2016, a 5-year follow-up with the same questionnaire was performed in survivors.ResultsFifty-two (36.5% women) of 74 patients (91%) treated with oxaliplatin and 80 (100% women) of 100 patients (85%) treated with docetaxel answered the questionnaire. The most common symptoms of CIPN were tingling in the hands (44.2% in the oxaliplatin (CI 95% 30.5; 58.7) and 36.3% in the docetaxel group (CI 95% 25.8; 47.8)) and feet (52.0% in the oxaliplatin (CI 95% 37.6; 66.0) and 37.5% (CI 95% 29.9; 49.0) in the docetaxel group) and numbness in the feet (34.6% in the oxaliplatin (CI 95% 22.0; 49.1) and 17.5% (CI 95% 9.9; 27.6) in the docetaxel group). Pain was present in the hands or feet in 28.9% of patients treated with oxaliplatin (CI 95% 17.12; 43.0) and 31.3% of patients treated with docetaxel (CI 95% 21.3; 42.6).ConclusionsThe results showed no major change in symptoms of neuropathy or pain from 1 to 5 years after chemotherapy. Symptoms of neuropathy were more common in patients treated with oxaliplatin.

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Li, Daxian, Ji Lee, Chang Choi, Jaihwan Kim, Sun Kim, and Woojin Kim. "The Analgesic Effect of Venlafaxine and Its Mechanism on Oxaliplatin-Induced Neuropathic Pain in Mice." International Journal of Molecular Sciences 20, no. 7 (April 3, 2019): 1652. http://dx.doi.org/10.3390/ijms20071652.

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The analgesic effect of venlafaxine (VLX), which is a selective serotonin and noradrenaline reuptake inhibitor (SNRI), has been observed on oxaliplatin-induced neuropathic pain in mice. Significant allodynia was shown after oxaliplatin treatment (6 mg/kg, i.p.); acetone and von Frey hair tests were used to assess cold and mechanical allodynia, respectively. Intraperitoneal administration of VLX at 40 and 60 mg/kg, but not 10 mg/kg, significantly alleviated these allodynia. Noradrenaline depletion by pretreatment of N-(2-Chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, 50 mg/kg, i.p.) blocked the relieving effect of VLX (40 mg/kg, i.p.) on cold and mechanical allodynia. However, serotonin depletion by three consecutive pretreatments of para-chlorophenylalanine (PCPA, 150 mg/kg/day, i.p.) only blocked the effect of VLX on mechanical allodynia. In cold allodynia, the α2-adrenergic antagonist idazoxan (10 μg, i.t.), but not the α1-adrenergic antagonist prazosin (10 μg, i.t.), abolished VLX-induced analgesia. Furthermore, idazoxan and 5-HT3 receptor antagonist bemesetron (MDL-72222, 15 μg, i.t.), but not prazosin or mixed 5-HT1, 2 receptor antagonist methysergide (10 μg, i.t.), abolished VLX-induced analgesia in mechanical allodynia. In conclusion, 40 mg/kg of VLX treatment has a potent relieving effect against oxaliplatin-induced neuropathic pain, and α2-adrenergic receptor, and both α2-adrenergic and 5-HT3 receptors are involved in this effect of VLX on cold and mechanical allodynia, respectively.

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Dong, Zhi-Bin, Yu-Jia Wang, Meng-Lin Cheng, Bo-Jun Wang, Hong Lu, Hai-Li Zhu, Ling Liu, and Min Xie. "2-Bromopalmitate decreases spinal inflammation and attenuates oxaliplatin-induced neuropathic pain via reducing Drp1-mediated mitochondrial dysfunction." PLOS ONE 17, no. 10 (October 31, 2022): e0275428. http://dx.doi.org/10.1371/journal.pone.0275428.

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Oxaliplatin (OXA) is a third-generation platinum compound with clinical activity in multiple solid tumors. Due to the repetition of chemotherapy cycle, OXA-induced chronic neuropathy presenting as paresthesia and pain. This study explored the neuropathy of chemotherapy pain and investigated the analgesic effect of 2-bromopalmitate (2-BP) on the pain behavior of OXA-induced rats. The chemotherapy pain rat model was established by the five consecutive administration of OXA (intraperitoneal, 4 mg/kg). After the establishment of OXA-induced rats, the pain behavior test, inflammatory signal analysis and mitochondrial function measurement were conducted. OXA-induced rats exhibited mechanical allodynia and spinal inflammatory infiltration. Our fluorescence and western blot analysis revealed spinal astrocytes were activated in OXA rats with up-regulation of astrocytic markers. In addition, NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome mediated inflammatory signal cascade was also activated. Inflammation was triggered by dysfunctional mitochondria which represented by increase in cyclooxygenase-2 (COX-2) level and manganese superoxide dismutase (Mn-SOD) activity. Intrathecally injection of 2-BP significantly attenuated dynamin-related protein 1 (Drp1) mediated mitochondrial fission, recovered mitochondrial function, suppressed NLRP3 inflammasome cascade, and consequently decreased mechanical pain sensitivity. For cell research, 2-BP treatment significantly reversed tumor necrosis factor-α (TNF-α) induced mitochondria membrane potential deficiency and high reactive oxygen species (ROS) level. These findings indicate 2-BP decreases spinal inflammation and relieves OXA-induced neuropathic pain via reducing Drp1-mediated mitochondrial dysfunction.

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Durand, J. P., G. Deplanque, J. Gorent, V. Montheil, E. Raymond, F. Scotte, E. Mitry, and F. Goldwasser. "Efficacy of venlafaxine for the prevention and relief of acute neurotoxicity of oxaliplatin: Results of EFFOX, a randomized, double-blinded, placebo-controlled prospective study." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 9533. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.9533.

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9533 Background: Neurosensory toxicity of oxaliplatin is dose-limiting and presents as two distinct clinical syndromes: acute symptoms and cumulative peripheral neuropathy. Methods: From October 2005 to May 2008, patients (pts) presenting oxaliplatin-induced acute neurotoxicity were randomized in a double-blinded study, to receive either arm A: venlafaxine hydrochloride (Effexor, Wyeth Pharmaceuticals Inc.) 50 mg 1 hour prior oxaliplatin infusion and venlafaxine extended release 37.5 mg b.i.d. from day 2 to day 11, either arm B : placebo. The primary endpoint was percentage of pts without acute neuropathy. The study was designed to detect, with 54 pts, a difference of 25%. The neurotoxicity was evaluated using a numeric rating scale of symptoms relief and the Neuropathic Pain Symptom Inventory (Pain 2004;108(3):248–57). Results: 45 pts were included (male : 24; median age : 67.5). Most pts had colo-rectal cancer (75.6%). The two most used chemotherapy regimens were FOLFOX (82.2%) and GEMOX (11.1%). Median number of cycles administered at inclusion was 5. In January 2009, 16 pts out of 22 in arm A (venlafaxine) and 21 pts out of 23 in arm B (placebo) were evaluable. Venlafaxine reduced the incidence of neurosensory acute symptoms : 35.3 % in arm A vs 76.2% in arm B (p=.023, Fisher's exact test). Side effects were emesis (4 pts) and somnolence (3 pts). Conclusions: Venlafaxine is effective for prevention and relief of oxaliplatin-induced acute neurotoxicity. No significant financial relationships to disclose.

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Selvy, Marie, Bruno Pereira, Nicolas Kerckhove, Coralie Gonneau, Gabrielle Feydel, Caroline Pétorin, Agnès Vimal-Baguet, et al. "Long-Term Prevalence of Sensory Chemotherapy-Induced Peripheral Neuropathy for 5 Years after Adjuvant FOLFOX Chemotherapy to Treat Colorectal Cancer: A Multicenter Cross-Sectional Study." Journal of Clinical Medicine 9, no. 8 (July 27, 2020): 2400. http://dx.doi.org/10.3390/jcm9082400.

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(1) Background: Oxaliplatin is among the most neurotoxic anticancer drugs. Little data are available on the long-term prevalence and consequences of chemotherapy-induced peripheral neuropathy (CIPN), even though the third largest population of cancer survivors is made up of survivors of colorectal cancer. (2) Methods: A multicenter, cross-sectional study was conducted in 16 French centers to assess the prevalence of CIPN, as well as its consequences (neuropathic pain, anxiety, depression, and quality of life) in cancer survivors during the 5 years after the end of adjuvant oxaliplatin chemotherapy. (3) Results: Out of 406 patients, the prevalence of CIPN was 31.3% (95% confidence interval: 26.8–36.0). Little improvement in CIPN was found over the 5 years, and 36.5% of patients with CIPN also had neuropathic pain. CIPN was associated with anxiety, depression, and deterioration of quality of life. None of the patients with CIPN were treated with duloxetine (recommendation from American Society of Clinical Oncology), and only 3.2%, 1.6%, and 1.6% were treated with pregabalin, gabapentin, and amitriptyline, respectively. (4) Conclusions: Five years after the end of chemotherapy, a quarter of patients suffered from CIPN. The present study showed marked psychological distress and uncovered a failure in management in these patients.

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Chuang, Yu-Chia, Cheng-Han Lee, Wei-Hsin Sun, and Chih-Cheng Chen. "Involvement of advillin in somatosensory neuron subtype-specific axon regeneration and neuropathic pain." Proceedings of the National Academy of Sciences 115, no. 36 (August 20, 2018): E8557—E8566. http://dx.doi.org/10.1073/pnas.1716470115.

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Advillin is a sensory neuron-specific actin-binding protein expressed at high levels in all types of somatosensory neurons in early development. However, the precise role of advillin in adulthood is largely unknown. Here we reveal advillin expression restricted to isolectin B4-positive (IB4+) neurons in the adult dorsal root ganglia (DRG). Advillin knockout (KO) specifically impaired axonal regeneration in adult IB4+ DRG neurons. During axon regeneration, advillin was expressed at the very tips of filopodia and modulated growth cone formation by interacting with and regulating focal-adhesion–related proteins. The advillin-containing focal-adhesion protein complex was shed from neurite tips during neurite retraction and was detectable in cerebrospinal fluid in experimental autoimmune encephalomyelitis, oxaliplatin-induced peripheral neuropathy, and chronic constriction injury of the sciatic nerve. In addition, advillin KO disturbed experimental autoimmune encephalomyelitis-induced neural plasticity in the spinal-cord dorsal horn and aggravated neuropathic pain. Our study highlights a role for advillin in growth cone formation, axon regeneration, and neuropathic pain associated with IB4+ DRG neurons in adulthood.

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Dziubina, Anna, Anna Rapacz, Anna Czopek, Małgorzata Góra, Jolanta Obniska, and Krzysztof Kamiński. "Antinociceptive and Antiallodynic Activity of Some 3-(3-Methylthiophen-2-yl)pyrrolidine-2,5-dione Derivatives in Mouse Models of Tonic and Neuropathic Pain." International Journal of Molecular Sciences 23, no. 7 (April 6, 2022): 4057. http://dx.doi.org/10.3390/ijms23074057.

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Antiseizure drugs (ASDs) are commonly used to treat a wide range of nonepileptic conditions, including pain. In this context, the analgesic effect of four pyrrolidine-2,5-dione derivatives (compounds 3, 4, 6, and 9), with previously confirmed anticonvulsant and preliminary antinociceptive activity, was assessed in established pain models. Consequently, antinociceptive activity was examined in a mouse model of tonic pain (the formalin test). In turn, antiallodynic and antihyperalgesic activity were examined in the oxaliplatin-induced model of peripheral neuropathy as well as in the streptozotocin-induced model of painful diabetic neuropathy in mice. In order to assess potential sedative properties (drug safety evaluation), the influence on locomotor activity was also investigated. As a result, three compounds, namely 3, 6, and 9, demonstrated a significant antinociceptive effect in the formalin-induced model of tonic pain. Furthermore, these substances also revealed antiallodynic properties in the model of oxaliplatin-induced peripheral neuropathy, while compound 3 attenuated tactile allodynia in the model of diabetic streptozotocin-induced peripheral neuropathy. Apart from favorable analgesic properties, the most active compound 3 did not induce any sedative effects at the active dose of 30 mg/kg after intraperitoneal (i.p.) injection.

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Zhang, Haowen, and Hongping Chen. "TRPA1 involved in miR-141-5p-alleviated neuropathic pain induced by oxaliplatin." NeuroReport 32, no. 3 (February 3, 2021): 284–90. http://dx.doi.org/10.1097/wnr.0000000000001589.

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Ito, Naomi, Atsushi Sakai, Noriko Miyake, Motoyo Maruyama, Hirotoshi Iwasaki, Koichi Miyake, Takashi Okada, Atsuhiro Sakamoto, and Hidenori Suzuki. "miR-15b mediates oxaliplatin-induced chronic neuropathic pain through BACE1 down-regulation." British Journal of Pharmacology 174, no. 5 (January 23, 2017): 386–95. http://dx.doi.org/10.1111/bph.13698.

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Li, Daxian, Woojin Kim, and Sun Kwang Kim. "The analgesic effects of venlafaxine on oxaliplatin induced neuropathic pain in mice." IBRO Reports 6 (September 2019): S113. http://dx.doi.org/10.1016/j.ibror.2019.07.363.

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Matsuura, Kae, Atsushi Sakai, Yuji Watanabe, Yasunori Mikahara, Atsuhiro Sakamoto, and Hidenori Suzuki. "Endothelin receptor type A is involved in the development of oxaliplatin-induced mechanical allodynia and cold allodynia acting through spinal and peripheral mechanisms in rats." Molecular Pain 17 (January 2021): 174480692110580. http://dx.doi.org/10.1177/17448069211058004.

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Oxaliplatin, a platinum-based chemotherapeutic agent, frequently causes severe neuropathic pain typically encompassing cold allodynia and long-lasting mechanical allodynia. Endothelin has been shown to modulate nociceptive transmission in a variety of pain disorders. However, the action of endothelin varies greatly depending on many variables, including pain causes, receptor types (endothelin type A (ETA) and B (ETB) receptors) and organs (periphery and spinal cord). Therefore, in this study, we investigated the role of endothelin in a Sprague–Dawley rat model of oxaliplatin-induced neuropathic pain. Intraperitoneal administration of bosentan, a dual ETA/ETB receptor antagonist, effectively blocked the development or prevented the onset of both cold allodynia and mechanical allodynia. The preventive effects were exclusively mediated by ETA receptor antagonism. Intrathecal administration of an ETA receptor antagonist prevented development of long-lasting mechanical allodynia but not cold allodynia. In marked contrast, an intraplantar ETA receptor antagonist had a suppressive effect on cold allodynia but only had a partial and transient effect on mechanical allodynia. In conclusion, ETA receptor antagonism effectively prevented long-lasting mechanical allodynia through spinal and peripheral actions, while cold allodynia was prevented through peripheral actions.

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Journal articles on the topic 'Oxaliplatin-induced neuropathic pain'

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