Ereditary Sensory and Autonomic Neuropathies

Frontiers of Pain

The Study of Hereditary Sensory and Autonomic Neuropathies in Understanding and Treating Pain

Congenital insensitivity to pain is a rare genetic disorder that is classified as hereditary sensory and autonomic neuropathy type-IV. Such afflicted individuals lack the peripheral and physiological mechanisms for experiencing pain. The study of patients suffering from this condition has led researchers to begin to understand the role of genetics in pain sensation and regulation. In addition, manipulation of genes identified with pain modulation provides further insight to physiological mechanisms. The experiment examined demonstrates the application of what has been learned from such studies and the clinical implications. The results of the study showed that peripheral insertion of an altered gene into sensory cells enabled artificial manipulation of pain sensation. It is important to understand the benefits and opportunities of studying such pain disorders.

The sensation of pain is integral for human survival and the development of appropriate behaviors.  Like many other sensations, pain clearly has an evolutionary purpose; to facilitate the prevention of harmful actions and provide a warning that physiologically something might be damaged or in need of attention.  Pain sensation of tissue damage is called nociception as it originates from touch receptors called A-delta and C nociceptors (Wolfe, J. M., Kluender, K. R., Levi, D. M., Bartoshuk, L. M., Herz, R. S., Klatzky, R. L., 2006, p. 292).  Although pain exists for a reason it causes much discomfort and distress which should be treated, especially when it is the product of diseases such as neuropathy or cancer.

Many case study investigations have identified hereditary sensory and autonomic neuropathies (HSAN) characterized by the impairment of nociception and the sensory-discriminative component of pain perception (Nagasako, EM, Oaklander, AL, & Dworkin, RH., 2003).  These neuropathies produce a continuum of pain sensation abnormalities, the extreme end of which is associated with congenital insensitivity to pain with anhidrosis (CIPA).  Subjects with CIPA (HSAN IV) exhibit an absence of unmyelinated C and myelinated A-delta fibers which causes an insensitivity to pain while preserving touch and pressure sensitivity (Nagasako et al., 2003).  This incurable condition is devastating as it prevents individuals from discerning whether internal or external damage has been done that could be life threatening.  However, since CIPA is a genetic condition specifically correlated with mutations in genes coding for nerve growth factor receptors (Indo, Y., 2002), investigations provide insight for a better understanding of sensory pathways and mechanisms involved with pain.  In addition, the studies of HSAN and CIPA subjects have clinical implications for new pain treatment and therapy (Indo, Y., 2002).

The identification of the gene mutations responsible for CIPA as well as the other HSANs has opened many potential doors to the study of pain.  Understanding the genetic aspect of these disorders leads to the interpretation of those specific genes and their involvement in normal pain sensation.  In a CIPA patient the mutation of the TrkA gene causes impairment to nerve growth factor (NGF) receptors on nociceptors which results in apoptosis of the associated sensory cells during development (Serý, O, Hrazdilová, O, Matalová, E, et al., 2005).  Further study on the purpose of this recently identified gene has shown that TrkA receptors for NGF also function in neuropeptide expression in nociceptors (Serý, O, et al., 2005).  Primary sensory neurons such as A-delta and C fibers that regulate pain transduction are affected by these neuroactive peptides; thus, changes to this system can alter pain sensation (Serý, O, et al., 2005).  What if this information could be used to locally suppress pain sensation in afflicted individuals?  Steps are already being taken toward the development of this type of pain therapy.  In one study by Wilson, SP, & Yeomans, DC. (2002), recombinant herpes viruses were used to deliver altered genes to sensory neurons in an effort to modulate nociception.

ereditary Sensory and Autonomic Neuropathies Primary Data Analysis

Wilson, SP, & Yeomans, DC. (2002) designed an experiment in which artificial regulation of nociception was attempted.  The aim was to insert into specific sensory cells a transgene that coded for either the suppression or the overexpression of certain neural peptides which would decrease the release of the primary excitatory neurotransmitter glutamate.  In particular, a transgene coding for opioid peptides would cause activation of opioid receptors in turn lowering the release of glutamate.  If this could be achieved, nociception would be reduced.  This experiment would involve mice, but the implications for chronic pain therapy in humans would be incredibly beneficial.

Wilson, SP, & Yeomans, DC. (2002) were able to achieve delivery of transgenes by use of recombinant herpes viruses.  The herpes simplex virus carrying the transgene naturally enters dorsal root ganglion cells and becomes latent.  The cells could be infected locally and could be labeled, allowing for selectivity.  With this method, 100-200 ganglion neurons were infected and labeled in the mouse hindfoot.  The expression of the transgene lasted about six weeks but it decreased over time, remaining high for only two weeks.  The virus encoded for the overexpression of preproenkaphalin, an opioid peptide precursor.  This was expressed and the precursors did become the actual peptides.  With the success of the method, mice with viral application to their feet were tested for nociception.

 The mice infected with the transgene carrying virus were tested for foot withdrawal latency versus a control group of mice infected with a virus lacking the transgene.  Essentially they measured how long it took before the mice would move their foot away from noxious stimuli.  Two sets of tests were performed to the feet of the mice.  The first was administration of low and high intensity heating which are mediated by C and A-delta nociceptors respectively.  The second was the application of capsaicin and dimethylsulfoxide (also mediated by C and A-delta nociceptors respectively).  The two chemicals in the latter set of tests cause hyperalgesia, an extreme sensitivity to pain (Wolfe JM, et al., 2006).  This heightened sensitivity to pain can be compared to neuropathic pain in humans. 

The experiment yielded interesting and exciting results.  The baseline foot-withdrawal latency was not affected in the administration of heat.  However, the mice infected with the proenkephalin virus in the hyperalgesic tests were observed as having the hyper sensitive state quickly reversed or blocked.  These same mice exhibited the resistance to the hyper sensitive state for up to 14 after infection.  In addition, the infection and its effects were reversible. 

This research is important in that the methods and approaches could eventually be implemented in humans.  The same overproduction of opioid peptide precursors could provide therapy for humans with conditions causing hyperalgesic states.  However, because it was an experiment with mice it cannot be assumed that it would play out the same way in a human.  This experiment’s application is limited to mice. Future studies would include primate and human subjects, as well as production manipulation of other neural peptides.


Although the existence of hereditary sensory and autonomic neuropathies causes distress to many, it has provided insight and opportunities for research in newly unfolding aspects of pain sensation.  Clearly the Wilson SP, et al., (2002) experiment has demonstrated the therapeutic applications for understanding the genetic aspect of nociceptive regulation.  There are many other similar studies that have been conducted since and are still being investigated, all of which may give rise to new methods of mediating pain in humans.  For example, it was demonstrated that “overexpression of proenkephalin A in primary sensory neurons induced antinociceptive effects in persistent pain of inflammatory, neuropathic and cancerous origins” (Pohl, M, & Meunier, A., 2003).  A multitude of new ideas for research on the role of genetics in pain sensation has been sparked since the discovery of the genes responsible for CIPA, which will continue to be explored in future research.

Presently, the study of patients suffering from HSANs continues to expand our understanding of pain. Recently a 32 year old CIPA subject reported pain for the first time after the loss of her brother.  The case study was said to suggest that physical pain can occur in the absence of the biological means for nociception as a result of emotional distress (Danziger, N(1), & DANZIGER., 2005).  Further study of these patients via fMRI and brain imaging techniques may solidify hypotheses regarding many such dimensions of pain other than genetics.  The frontiers are vast, and we have so much more to understand.


Danziger, N(1), & DANZIGER. (2005). Tension-type headache as the unique pain experience of a patient with congenital insensitivity to pain. Pain, 117(3), 478-483.

Indo, Y. (2002). Genetics of congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV. Clinical, biological and molecular aspects of mutations in TRKA(NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor. Clinical autonomic research, 12 Suppl 1

Nagasako, EM, Oaklander, AL, & Dworkin, RH. (2003). Congenital insensitivity to pain: an update. Pain, 101(3), 213-9.

Pohl, M, & Meunier, A. (2003). Experimental gene therapy of chronic pain. Currentopinion in anaesthesiology, 16(5), 547-51.

Serý, O, Hrazdilová, O, Matalová, E, et al. (2005). Pain research update from a geneticpoint of view. Pain practice, 5(4), 341-8.

Wilson, SP, & Yeomans, DC. (2002). Virally mediated delivery of enkephalin and otherneuropeptide transgenes in experimental pain models. Annals of the New York Academy of Sciences, 971, 515-21.

Wolfe, J. M., Kluender, K. R., Levi, D. M., Bartoshuk, L. M., Herz, R. S., Klatzky, R. L.,et al. (2006). Sensation & Perception Sunderland, Massachusetts USA: Sinauer Associates, Inc.