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.
Discussion
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.
References
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.
