Understanding Chemotherapy Induced Neuropathic Pain with iPSC Derived Sensory Neurons

Although providing life-saving care, many widely used chemotherapy drugs can also come with unpleasant side effects and complications, including neuropathic pain which can be particularly debilitating. The treatments currently being used for neuropathic pain, such as anti-depressants and anti-seizure drugs, were originally approved for other health disorders and often have their accompanying problems.

Since no single drug is effective against all forms of neuropathic pain, it is vital that new therapeutic agents are researched and developed specifically for the treatment of this condition.

Researchers are increasingly turning to iPSC-derived sensory neurons to form a better understanding of neuropathic pain disorders. They offer a more biologically and physiologically relevant model system, with the promise of developing effective treatments to eliminate the suffering that is a daily part of the lives of the many individuals worldwide who are affected with the condition.

This article will discuss:

  • Neuropathic pain and nociceptive pain are different pain categorizations
  • Mechanisms by which chemotherapy causes the development of neuropathic pain
  • Chemotherapy is a major cause of neuropathic pain
  • iPSC-derived sensory neurons for studying neuropathic pain

Neuropathic Pain and Nociceptive Pain are Different Pain Categorizations

Neuropathic pain is a chronic condition that can be directly linked to 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, making the patient hypersensitive to cold, causing pain and numbness in the hands and feet, as well as making it difficult to swallow or breathe.

There are a variety of pathophysiologies that are a product of the specific chemotherapeutic agents. As well as hypersensitivity to various stimuli, there are sensory disorders that can produce sensations ranging from light tingling to a spontaneous burning pain. Whilst more likely to happen during chemotherapy, these may also occur after the treatment has ended, indicating ongoing neuronal damage. This example shows just how critical it is that these symptoms can be monitored and treated.

Mechanisms by Which Chemotherapy Causes the Development of Neuropathic Pain

There are several hypotheses on the role of chemotherapeutic drugs in the instigation and development of neuropathic pain. One possible etiology is mitochondrial dysfunction, given credence through the observation of significant increases in the amount of atypical mitochondria in the C-fibers and myelinated axons of nerves derived from Paclitaxel-treated rats.

Another potential cause may be how cell signaling mediators such as cytokines, growth factors and ion channels are altered post-drug administration. For instance, circulating levels of nerve growth factor in a rat model of neurotoxicity have shown to correlate with neuron damage which was caused by Cisplatin, another platinum-based chemotherapy.

A further postulation on neuropathic pain is the role of abnormal spontaneous activity in A and C fibers, which carry nociception. The fibers of rats treated with Paclitaxel or Vincristine show significantly greater spontaneous discharge in A-fiber and C-fiber primary afferent neurons compared to those untreated control animals. Prophylactic treatment with acetyl-L-carnitine, known to block Paclitaxel-induced neuropathic pain, could reduce this discharge.

iPSC-Derived Sensory Neurons for Studying Neuropathic Pain

Studies into the pathogenesis of neuropathic pain have traditionally used immortalized neuronal cell lines or animal models. A known problem with the use of immortalized cell lines is that they often exhibit a significant genotypic and phenotypic drift from the original donor. Animal models carry ethical considerations, on top of being expensive to perform and do not always translate into humans.

A more relevant system for researching neuropathic pain is available in the form of iPSC-derived sensory neurons. The iPSC-sensory neuron progenitors produced by AXOL are derived from integration-free iPSCs of a healthy male donor and have been differentiated to dorsal root ganglion neurons. They are well suited for nociception work as they express voltage-gated sodium ion channels and transient receptor potential (TRP) ion channels and can be procured 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.

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MATURATION MAXIMIZER is a fully defined media supplement to enhance the existing sensory neuron maintenance medium (ax0060) and  works by mimicking in-vitro, the cell to cell communication and interaction factors which occur when these cells are in their innate environment. The supplement is known to contain factors present in the peripheral nervous system and in particular the peripheral environment of sensory neurons."

About AXOL Biosciences

Axol specializes in human cell culture.

Axol produces high quality human cell products and critical reagents such as media and growth supplements. We have a passion for great science, delivering epic support and innovating future products to help our customers advance faster in their research.

Our expertise includes reprogramming cells to iPSCs and then differentiating to various cell types. We supply differentiated cells derived from healthy donors and patients of specific disease backgrounds. As a service, we also take cells provided by customers (primary or iPSC) and then do the reprogramming (when necessary) and differentiation. Clearly, by offloading the burden of generating cells, your time is freed up to focus on the research. Axol holds the necessary licenses that are required to do iPSC work.

The package wouldn't be complete without optimized media, coating solutions and other reagents. Our in-house R&D team works hard to improve on existing media and reagents as well as innovate new products for human cell culture. We also supply a growing range of human primary cells; making Axol your first port of call for your human cell culture needs.

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Last updated: Feb 18, 2020 at 11:28 AM


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