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Understanding the mechanisms of chemotherapy induced neuropathic pain using iPSC-derived sensory neurons

Understanding the mechanisms of chemotherapy induced neuropathic pain using iPSC-derived sensory neurons


Many commonly used chemotherapy drugs cause unpleasant side effects and complications.

Of these, neuropathic pain can be particularly debilitating. Most of the current treatments for neuropathic pain are medications that were originally approved for other health disorders, such as anti-depressants and anti-seizure drugs. These have their own accompanying problems, and since no single drug is effective against all forms of neuropathic pain, it is essential that new therapeutic agents are developed specifically for the treatment of this condition.

To better understand neuropathic pain disorders, researchers are turning to iPSC-derived sensory neurons. These represent a biologically and physiologically relevant model system, offering the promise of developing effective treatment options to improve the lives of the many individuals worldwide who are affected with the condition.

Neuropathic pain and nociceptive pain are different pain categorizations

Neuropathic pain is a chronic condition that occurs as a direct consequence of injury to nerve fibers. The cause of neuropathic pain includes trauma, vascular malformations, HIV, multiple sclerosis, vitamin deficiencies, diabetes and various cancer treatments. The incidence of neuropathic pain in the population is highly likely to rise due to factors such as increased life expectancy, greater prevalence of diabetes and improved survival from cancer following chemotherapy.

Nociceptive pain is associated with tissue damage and results from thermal, mechanical or chemical stimulation of specialized peripheral sensory neurons known as nociceptors. Although nociceptive pain is typically more short-lived than neuropathic pain, an example being the type of pain that is experienced following a superficial burn, nociceptors are also implicated in chronic pain conditions. These include those related to chemotherapy treatments.

Chemotherapy is a major cause of neuropathic pain

Many individuals with cancer experience pain because of a tumor exerting pressure on nerves, as a side-effect of radiotherapy treatment or due to chemotherapy-related neurotoxicities. The latter can be a dose-limiting factor in treatment regimens, leading to dose reduction or even a discontinuation of chemotherapy. Oxaliplatin is a prime example where a platinum-based chemotherapy used to treat advanced colorectal cancer is dose-limited by neurosensory toxicity . This manifests as cold dysesthesia, a hypersensitivity to cold which can cause pain and numbness in the hands and feet, as well as severe difficulty in swallowing or breathing.

Other chemotherapeutic agents have different pathophysiologies. In addition to hypersensitivity to various stimuli, sensory disorders can include sensations ranging from mild tingling to a spontaneous burning pain . These can occur during chemotherapy and even after the treatment has ended, indicating ongoing neuronal damage once drug administration is complete. It is therefore essential to be able to monitor and treat these symptoms.

Mechanisms by which chemotherapy causes the development of neuropathic pain

Several hypotheses have been suggested to explain how chemotherapeutic drugs cause the onset and development of neuropathic pain. One possible etiology is mitochondrial dysfunction, which is supported by the observation of significant increases in the number of atypical mitochondria in the C-fibers and myelinated axons of nerves derived from Paclitaxel-treated rats. Another potential cause relates to changes in cell signaling mediators such as cytokines, growth factors and ion channels. For instance, circulating levels of nerve growth factor in a rat model of neurotoxicity have been shown to correlate with neuron damage caused by Cisplatin, another platinum-based chemotherapy.

A further postulation is that abnormal spontaneous activity in A and C fibers, which carry nociception, may play a role in neuropathic pain. The fibers of rats treated with Paclitaxel or Vincristine have demonstrated significantly greater spontaneous discharge in A-fiber and C-fiber primary afferent neurons than those of untreated control animals. This discharge could be reduced by prophylactic treatment with acetyl-L-carnitine, known to block Paclitaxel-induced neuropathic pain.

iPSC-derived sensory neurons for studying neuropathic pain

Many studies into the pathogenesis of neuropathic pain have relied on immortalized neuronal cell lines or animal models. A widespread concern with the use of immortalized cell lines is that many exhibit a considerable genotypic and phenotypic drift from the original donor, while the use of animal models has ethical considerations. Animal studies are also expensive to perform and do not always translate into humans.

iPSC-derived sensory neurons represent a more relevant system for researching neuropathic pain. Our iPSC-sensory neuron progenitors are derived from integration-free iPSCs of a healthy male donor and have been differentiated to dorsal root ganglion neurons. They express voltage-gated sodium ion channels and transient receptor potential (TRP) ion channels that play a key role in nociception and are available in large batch sizes for reliable and consistent results . They are backed by a wealth of data that includes ion channel expression analysis, Na v 1.7 and Na v 1.8 immunocytochemistry, and evaluation of electrical activity .

take your pain research to the next level with Axol’s human iPSC-derived sensory neurons

Layers of complexity: differentiating iPSCs into derivatives of the embryonic germ layers
iPSC-derived sensory neurons for the study of chemotherapy-induced neuropathic pain