The increasing incidence of malignant tumors has led to a growing reliance on chemotherapy drugs as first-line antitumor agents. Platinum-based drugs are the main chemotherapeutic agents for treating Colorectal cancer (CRC) (Cartwright and Cunningham, 2017). Statistics show that approximately 65%–98% of chemotherapy patients develop peripheral neuropathy following oxaliplatin treatment (Cavaletti and Marmiroli, 2020). Oxaliplatin, a third-generation platinum-based cytotoxic derivative, is primarily used to treat advanced colorectal cancer and is considered to have a more favorable safety profile compared to other platinum-based agents (Sałat et al., 2019a). However, its side effects significantly compromise patients’ quality of life. Oxaliplatin therapy is primarily linked to three dose-limiting toxicities: neurotoxicity (notably oxaliplatin-induced peripheral neuropathy, OIPN), myelosuppression, and gastrointestinal problems (Marmiroli et al., 2017). These adverse effects significantly influence therapy success, especially considering the characteristic dose-dependent course of OIPN that often requires treatment alteration. Oxaliplatin exhibits a mechanism of action that is fundamentally different from traditional platinum-based chemotherapeutics, as its cumulative neurotoxicity shows clinically meaningful reversibility after treatment discontinuation, a neuroprotective characteristic absent in cisplatin-class drugs (Starobova and Vetter, 2017).

Chemotherapy-induced neuropathic pain (CINP)is a debilitating, dose-limiting toxicity of cancer chemotherapy. This neuropathy not only markedly diminishes quality of life but also often compels patients to modify or discontinue their treatment, presenting a significant clinical challenge (Mantyh, 2006).

Despite its clinical relevance, the mechanisms underlying CINP remain poorly understood. Acute OIPN symptoms may present as dyspnea and dysphagia, whereas chronic OIPN clinical signs encompass distal sensory abnormalities, decreased proprioception, and diminished deep tendon reflexes (Marmiroli et al., 2017). However, the mechanisms underlying CIPNP (chemotherapy-induced peripheral neuropathy) have not yet been fully elucidated. OIPN is associated with alterations in voltage-gated Na⁺ channels, as well as K⁺ channels, Ca²⁺ channels, and transient receptor potential (TRP) channels. Abnormalities in voltage-gated Na⁺ channels lead to prolonged channel opening and excessive excitability of dorsal root ganglion (DRG) sensory neurons (Webster et al., 2005). These changes induce ectopic discharges, resulting in the typical symptoms of oxaliplatin-induced sensory abnormalities. Prior research by academics has demonstrated that OXA-induced cold hyperalgesia increases the production of TRPA1 protein on TRP channels. CINP induced by OXA intensifies oxidative stress, thus modulating TRPA1 and aggravating CINP symptoms (Lim et al., 2010). The principal factors contributing to chronic OIPN include nuclear DNA damage, mitochondrial impairment, excessive oxidative stress, and activation of glial cells (Staff et al., 2019). Furthermore, mitochondrial impairment significantly contributes to CINP produced by OXA. In vitro findings indicate that the mitochondrial structure and function of rat neural cells exposed to OXA are modified (Bobylev et al., 2018). The activation of neuroimmune responses is a significant role in the development of CINP. The aberrant activation between neurons and glial cells is essential for neuropathic pain.

According to the 2020–2021 clinical practice guidelines of the American Society of Clinical Oncology (ASCO), no preventive or therapeutic strategies have been definitively established for CINP(11). As such, the selection of suitable animal models for research is of paramount importance. Current mechanistic studies commonly employ rat or mouse models of CINP, yet the absence of clear classifications and standardized evaluation criteria hinders the optimal use of these models, thereby affecting the reliability and validity of research outcomes. While various therapeutic approaches exist for chronic pain, certain researchers have performed pain-relief tests on mice utilizing an individual intra-abdominal injection of oxaliplatin (3 mg/kg) in conjunction with milnacipran. The mechanical pain in these animals peaked 10 days post-injection. Nevertheless, the mechanical pain threshold in the mice was diminished following the administration of milnacipran (Hershman et al., 2014). In addition, ASCO only recommends duloxetine for treatment. Nevertheless, the aforementioned therapies still have many shortcomings and deficiencies. Therefore, it is urgent to seek more perfect animal models for clinical treatment.

This paper discusses the methodologies for establishing rat and mouse CINP models induced by oxaliplatin, along with specific evaluation techniques and their applications in clinical research. The objective is to provide more precise and effective approaches for advancing CINP research.

The common methods for establishing rat and mouse CINP models include intraperitoneal and intravenous injections. Both techniques are relatively safe and straightforward, with intraperitoneal injection being the predominant method used globally for CINP modeling (Al Moundhri et al., 2013). Clinical trials indicate that oxaliplatin-induced peripheral neuropathy (OIPN) is a cumulative adverse event, typically manifesting when the total oxaliplatin dose exceeds 750–850 mg/m² (Soveri et al., 2019; de Gramont et al., 2023). Prior research indicates that significant symptoms of oxaliplatin-induced chemotherapy-induced peripheral neuropathy during the acute phase correlate with similarly severe symptoms transitioning to the chronic phase in the initial treatment cycle (Pachman et al., 2015). Furthermore, the manifestations of oxaliplatin-induced CINP endure for an extended period. Post-chemotherapy, patients’ neuropathy persists and exacerbates due to the continued accumulation of oxaliplatin in the dorsal root ganglion (DRG) (Staff et al., 2019).

Rat CINP models are generally classified into acute and chronic types. Acute models involve a single or short-term high-dose injection of oxaliplatin, while chronic models utilize prolonged low-dose injections. Varying the injection dose and duration can induce different degrees of nerve damage. Research has demonstrated that a single intraperitoneal injection of oxaliplatin (6 mg/kg) reliably induces peripheral neuropathic pain in rats, primarily characterized by mechanical and cold allodynia (Baek et al., 2024).

Post-oxaliplatin treatment, rats exhibit several behavioral changes, including reduced food intake, weight loss, or stunted weight gain. Other signs may include limb muscle atrophy, increased paw licking, and paw lifting. Additionally, mechanical pain thresholds and cold/heat pain thresholds are altered. These behavioral manifestations serve as critical indicators for assessing the success of model establishment.

The table below offers a detailed summary of commonly employed acute and chronic modeling methods, along with their associated behavioral characteristics and safety assessments.

Oxaliplatin-induced neuropathic pain in clinical settings is characterized primarily by limb numbness, cold pain, and sensory disturbances. Approximately 80% of chemotherapy patients develop chemotherapy-induced peripheral neuropathy (CINP), with 60% continuing to experience symptoms 3 months post-treatment (Hu et al., 2019). These clinical manifestations are also evident in rat and mouse CINP models. Consequently, model evaluation typically involves assessing mechanical pain thresholds, mechanical allodynia, and alterations in cold and heat pain thresholds, along with cold/heat allodynia. The following are the evaluation methods most frequently used in recent studies.

CINP is predominantly characterized as a sensory neuropathy with symmetrical symptoms. Common clinical manifestations include numbness, proprioception loss or impairment, tingling, pricking sensations, and hyperalgesia or allodynia, often affecting the hands and feet in a “stocking-and-glove” distribution pattern (Park et al., 2013). Oxaliplatin-associated CINP presents acutely and exacerbates with successive chemotherapy cycles (Pachman et al., 2016). It is estimated that 65%–98% of chemotherapy patients receiving oxaliplatin develop peripheral neuropathy (Cavaletti and Marmiroli, 2020). Currently, there is no definitive treatment for CINP in Western medicine. The 2020–2021 guidelines from the ASCO recommend duloxetine for pain management (Loprinzi et al., 2020), though its limited efficacy and notable side effects underscore the need for alternative therapeutic strategies. Additional approaches, such as minimally invasive interventional treatments, physical therapy, and external therapies like acupuncture, have been explored for treating CINP(51). We have encapsulated the applications of rats and mice in simulating CINP, detailing specific methodologies, safety protocols, injection dosages, and additional considerations. The table delineates the modeling techniques for the CINP acute model in rats (Table 1), alongside its applicability across several rat types (Table 2), mice (Table 3), and the injection methodologies for both rats and mice (Table 4)(Figures 1,2, ).

OIPN can be classified into acute and chronic types, each driven by distinct mechanisms. Acute OIPN is linked to ion channel dysfunction, aberrant organic cation transporters, and glial cell abnormalities. In contrast, chronic OIPN mechanisms involve nuclear DNA damage, mitochondrial oxidative stress-induced injury, neuroinflammation through glial cell activation, and inflammation associated with gut microbiota disturbances (Yang et al., 2021). Chemotherapy-induced breakdown of the intestinal epithelial barrier results in the translocation of gut microbiota and the release of detrimental endogenous chemicals, thereby provoking the creation of pro-inflammatory mediators. This is a crucial element in the pathophysiology of CINP((Zhong et al., 2019)). Patients undergoing various chemotherapy regimens have encountered significant gut microbial dysbiosis. A notable decrease in bacteria, including Bacteroidetes, Bifidobacterium, and Clostridium clusters IV and XIVa, is observed (Zwielehner et al., 2011). Dorsal root ganglion (DRG) neurons express various ion channels, including voltage-gated sodium channels (Nav), potassium channels (Kv), calcium channels (Cav), chloride channels, and transient receptor potential (TRP) channels, all of which are integral to pain perception and intrinsic excitability regulation (Stevens and Stephens, 2018). Clinical studies in chronic OIPN have shown that 78% of patients present with abnormalities in Na + channels (Lee et al., 2013). The principal effects of chemotherapy-induced neurotoxicity are predominantly linked to cognitive impairment in the central nervous system in OIPN ((Cerulla Torrente et al., 2020)). The buildup of platinum-DNA adducts is regarded as a crucial element in the onset of OIPN((McWhinney et al., 2009)). Neuronal mitochondrial malfunction leading to nitro-oxidative stress is pivotal in OXA-induced neuropathy (Streckmann et al., 2018). (Figures 3–5).

Oxaliplatin treatment notably alters the expression of voltage-gated ion channels and genes involved in synaptic transmission in DRG neurons of rats (Housley et al., 2020). The activation of glial cells in the DRG, contributes to heightened inflammatory responses and increased neuronal excitability, ultimately leading to chemotherapy-induced hyperalgesia (Fumagalli et al., 2020). Oxaliplatin is believed to primarily induce apoptosis by forming DNA adducts (Yang et al., 2018). Investigations into the mechanisms underlying oxaliplatin-induced CINP focus on the pathological processes and molecular pathways in animal models, with oxidative stress playing a pivotal role in neuropathic injury.

Key indicators for evaluating and validating CINP in animal models include nociceptive abnormalities, particularly tactile allodynia thresholds assessed by electronic Von Frey testing. Neuropathic pain serves as a reliable marker for CINP severity in patients (Kerckhove et al., 2021; Selvy et al., 2021), and measuring nociceptive thresholds in live rodents offers convenience and high reproducibility (Turner et al., 2019). Selecting an appropriate animal model is thus essential for addressing research questions. Anti-inflammatory mechanisms are investigated in male Sprague-Dawley rats (on days 0, 2, and 4) (Miguel et al., 2019). Due to their simplicity in modeling, ease of behavioral assessment, and widespread use, rat and mouse CINP models have become crucial tools for studying human disease mechanisms and exploring preventive and therapeutic strategies, with significant potential for clinical applications. This work summarizes CINP models in multiple rodent species (rats and mice), detailing different dosages, pain detection techniques, and the safety of associated modeling approaches, with the objective of offering more accurate and clinically pertinent CINP models.

Animal models are commonly employed to investigate the mechanisms underlying CINP and, more importantly, to assess the efficacy of drugs in preventing or reversing CINP symptoms (Höke and Ray, 2014). While CINP has been reported to be more severe in female patients (Mizrahi et al., 2021), findings on sex differences in animal studies remain inconsistent. Some studies suggest more pronounced symptoms in males, while others report greater severity in females (Warncke et al., 2021). Therefore, future studies should incorporate both male and female animal models of CINP to improve the translational impact.

Moreover, further exploration is needed regarding factors such as chemotherapy drug type, dosage, administration route, animal model selection, and behavioral assessment methods to establish standardized experimental protocols. This will help reduce experimental bias and enable deeper investigations into current research topics, including DRG sensory neuron injury, ion channel dysfunction, and novel therapeutic approaches.

Considering the significant influence of oxaliplatin dosage on neuropathy and chemotherapeutic effectiveness, it is essential to investigate personalized precision treatment approaches further (Krishnan et al., 2005). At the typical therapeutic dosage, oxaliplatin not only precipitates neuropathy but may also result in extra adverse events. Research indicates that specific chemosensitizers can augment the therapeutic efficacy of oxaliplatin (Ge et al., 2016). Based on this, the dosage of oxaliplatin can be appropriately reduced when using sensitizers. Chemotherapy frequently induces peripheral neuropathy in cancer patients, a prevalent side effect that can severely affect their quality of life. It generally presents with symptoms including numbness, discomfort, and atypical feelings. Despite the availability of certain ways to mitigate these symptoms, CINP continues to pose a significant challenge for cancer patients. To effectively tackle this dilemma, there is an immediate necessity to create more accurate animal models. These models enable researchers to more effectively find novel therapeutic targets and clinical tactics, ultimately significantly enhancing the treatment experience for cancer patients.