Role of Neuregulin-1/ErbB Signaling in Stem Cell Therapy for Spinal Cord Injury-induced Chronic Neuropathic Pain.

The article by Tao et al. revisits an interesting area of research that is associated with a rather large and controversial literature. Historically, a number of different transplant models have been used in the study of spinal cord injury. Human spinal cord tissue was used previously in a safety trial, adrenal tissue along with designer cell lines (human and non-human), and Schwann cells to name a few have all been used in clinical and preclinical studies over a 15-year period where the intent has been to improve function while targeting many of the complications associated with spinal cord injury (SCI). Some approaches have shown promise, but there have also been those that have reported rather dramatic negative effects, including the development of allodynia and hyperalgesia. Given the questions surrounding the previous use of transplant strategies there is concern that the authors of the present study have neglected to provide a more scholarly appraisal of what is clearly a controversial area of research. Ideally one would like to see a successful intervention accomplish its intended goals, but at the same time pass the credibility test by being compatible with existing literature. The authors have failed to put their results in the context of what many would view as a significant history of transplant studies related to the study of pain following spinal cord injury.  

Another concern associated with the article by Tao and colleagues is how a large literature related to the study of pain associated with spinal cord injury has been largely ignored. For example, a recent report questioned the use of the contusion model in the study of pain associated with spinal injury (Baastrup et al., 2010). In the same report the authors also raised concerns over the use of reflex-based behavioral testing in the study of a cortically dependent sensation like pain. Interestingly, the authors have also chosen to ignore a number of studies comparing the use of reflex- versus operant-based methods, including the study by Baastrup and colleagues. Needless to say, the authors should be aware of the fact that the controversy over behavioral assessment in preclinical models of pain is not new. The current study represents a perfect example of how results obtained with a questionable behavioral method have been used to make strong and potentially influential statements about mechanisms, therapeutic targets and a potential strategy for a clinical intervention. One can’t help but wonder how different the conclusions might have been if another behavioral outcome had been used that produced not only a different but a totally opposite result. With regard to the present study there is no denying that a behavioral effect was observed following stem cell transplants. The dilemma one has with the study is the concern over whether the effects have anything to do with the condition of neuropathic pain or whether it is just another study dealing with the hyperactivity of spinal reflex circuits. The later possibility is certainly probable given the common observation of the spastic syndrome following spinal cord injury.

Finally, the authors seem to be promoting the idea that remyelination is responsible for the positive behavioral effects and equate the results with the alleviation of pain. This is an interesting conclusion which is directly dependent upon the behavioral outcome being a reliable measure of pain. If this is true one comes away with the belief that demyelination is a contributing factor in the development of SCI-induced abnormal sensation. This is an interesting proposal that many would agree will require a lot more evidence. Although there are concerns over the current study and there are well- documented controversial issues surrounding the use of transplants in the treatment of SCI, there remains optimism that continued research will provide the answers needed to develop more effective strategies to manage the challenges associated with SCI.

References:

Baastrup C, Maersk-Moller CC, Nyengaard JR, Jensen TS, Finnerup NB. Spinal-, brainstem- and cerebrally mediated responses at- and below-level of a spinal cord contusion in rats: evaluation of pain-like behavior. Pain. 2010 Dec;151(3):670-9.