Cell therapy as a cure for chronic pain

Figure 1. The stainless steel sculpture “Neuron” by Roxy Paine outside the Museum of Contemporary Art, Sydney. | Credit: Cristopher Neugebauer (Flickr).
Figure 1. The stainless steel sculpture “Neuron” by Roxy Paine outside the Museum of Contemporary Art, Sydney. | Credit: Cristopher Neugebauer (Flickr).

The way we approach pain therapies doesn’t differ from the ones taken for other diseases. The aim is to look for molecular targets, which can be suitable for chemical intervention thoroughly assessing both efficacy and safety profiles for the drug, issues that are addressed throughout various stages of clinical trials. In the specific case of pain, this approach is sensible when we are dealing with pain conditions in which the onset is acute, like the ones following an inflammatory process as a consequence of an infection or mild tissue damage (e.g. when you accidentally hit your thumb with a hammer). In these cases, taking a pill of ibuprofen may definitely help to relieve pain.

The problem arises when the pain condition is chronic and we have to deal with ongoing pain suffered by the patient for several months, or even years. Often, these conditions are the consequence of the development of neuropathic pain, which appears after damage in the nervous system (either central or peripheral). Typical examples are painful diabetic neuropathy, phantom limb pain (amputated patients) or multiple sclerosis, among others. The need for prolonged medication in these patients is obviously a handicap; when ibuprofen is taken for a long period of time there may be adverse effects on the kidney, clotting of blood and gastrointestinal system while opioids may lead to constipation, drowsiness, nausea, addiction and physical dependence.

Would there be then another way to tackle chronic pain? It seems that the answer is yes for at least some types of them. Previous studies have shown that cortical interneuron precursor transplantation into rodent adult forebrain leads to increased local GABA-mediated inhibition that ameliorates the symptoms seen in different models of epilepsy, specially those related to seizure by restoring synaptic inhibition. The grafted interneurons can disperse (travelling away from the region where they are injected) and create synapses leading to functional circuits 1. These interneurons are capable of restoring the imbalance between excitatory and inhibitory input, in this specific case by depressing the hyperexcitability phenotype observed in epileptic patients.

This observation led to the group of Allan I Basbaum in San Francisco to apply a similar therapy in the context of pain, because the loss of spinal cord dorsal horn inhibitory circuits involving GABAergic interneurons is likewise involved in the persistent neuropathic pain that appears as a consequence of nerve damage. This loss is accounted by a proportion of neurons undergoing apoptosis explain, at least partially by an NMDA-mediated excitotoxicity 2. The approach therefore consists on trying to heal part of the damage, instead of the typical pain mitigation strategy.

Accordingly, they used embryonic GABAergic cortical interneuron precursors from the medial ganglionic eminence (whose natural environment is the midbrain) grafted into the spinal cord hoping to see a recovery of the inhibitory pathway similarly to what happens in the central nervous system. Surprisingly, these precursors do survive and become GABAergic interneurons showing a phenotype consistent with their expected protein expression profile. In addition, the cells produce long processes within the spinal cord and create new connections with cells from the host tissue and more important they are able to receive input (to communicate) from primary afferents, this being the ultimate and more important goal from the study 3.

All previous data pointed to a full integration of the transplanted cells into the spinal cord, but as I have mentioned in previous posts, the ultimate proof showing the hypothesis is working is moving into in vivo experiments were mice carrying these brand new inhibitory neurons should revert the neuropathic pain. They decided to use a well-known model of neuropathic pain called the spared nerve injury model (SNI) in which part of the sciatic nerve is cut producing a prolonged and abnormally enhanced sensitivity to mechanical stimulus. So first, the model is established and once the mechanical pain appears, the progenitors are injected and monitored for recovery once a week for a month. A difference with the control (mice injected with medium but no cells) started to appear after two weeks matching the necessary time needed for the cells to differentiate into neurons. After a month, the pain was fully reversed. To further confirm these cells are just involved in the physiological transmission of pain they are supposed to be involved in, they used a model of inflammatory pain consisting of injecting a chemical molecule called formalin (also mentioned and explained in previous posts) in the paw of the mice. In this case, although a small reduction in pain response was seen, that was not significantly different to that from control mice, arguing against an impaired response of the newly integrated neurons.

Finally, and as a follow-up from the study I have just presented, they recently published a new one using a model of neuropathic itch that develops because of a mutation found in a transcription factor called Bhlhb5, involved in transcriptional regulation 4. In these mice, the itch is so severe that they inflict skin lesions to themselves because of excessive licking and scratching (mice even have to be euthanized after 7-8 weeks). The reason why they chose this model is because again, there is a substantial loss of inhibitory neurons, being therefore suitable for cell therapy intervention. Consistently, mice suffering the painful condition and developing severe skin lesions showed a huge improvement in their affected skin, even growing new hair in the affected area.

Despite of the early preclinical stage from these aforementioned studies, it is starting to become clear that once cell therapy becomes a safe and achievable way to treat disease, the versatility and possibilities it offers will surpass by far the current chemical intervention approaches, too often associated with side-effects and toxicity issues. It therefore means that often it may be a wrong choice, especially for those suffering from chronic pain, or any other chronic conditions requiring extended periods of medication.

References

  1. Southwell DG, Nicholas CR, Basbaum AI et al: Interneurons from embryonic development to cell-based therapy. Science 2014; 344: 1240622.
  2. Latremoliere A, Woolf CJ: Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 2009; 10: 895-926.
  3. Braz JM, Sharif-Naeini R, Vogt D et al: Forebrain GABAergic neuron precursors integrate into adult spinal cord and reduce injury-induced neuropathic pain. Neuron 2012; 74: 663-675.
  4. Braz JM, Juarez-Salinas D, Ross SE, Basbaum AI: Transplant restoration of spinal cord inhibitory controls ameliorates neuropathic itch. J Clin Invest 2014; 124: 3612-3616.

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