Monday, January 08, 2007

Hurts so good (from Neuroscience Gateway)

Hurts so good

Neuroscience Gateway (January 2007) | doi:10.1038/aba1705

Different mutations in the same sodium channel gene may cause
excessive pain or the inability to sense pain.

According to Goldilocks, just right lies between too little and too
much. The same principle can be applied to pain. People with too
little pain sensation often injure themselves, but too much pain can
be debilitating. Now researchers identify mutations in the same gene
that associate with too little and too much pain sensation in recent
articles in Nature and Neuron.

Nociceptive neurons of the dorsal root ganglion (DRG) express several
different sodium channels. The voltage-gated sodium channel Nav1.7,
encoded by SCN9A, is enriched in DRG neurons and helps sum the
activity of other sodium channels to generate action potentials,
which cause pain sensation.

Cox et al. identified SCN9A mutations in people in a northern
Pakistani clan who cannot sense pain, but have normal nerve
conduction and temperature and pressure sensation. By positional
cloning, the authors identified an 11.7 Mb region on chromosome 2
shared in all affected individuals in three related families. Finer
mapping failed to show a single haplotype in affected individuals,
suggesting that several mutations resulted in the same phenotype. The
authors sequenced SCN9A, the best candidate gene as shown by
bioinformatic analysis, and found discrete mutations in each family.
All of the mutations were 'nonsense' mutations that resulted in early
translation termination, presumably truncating Nav1.7.

Each SCN9A mutation rendered Nav1.7 nonfunctional. Cells transfected
with the mutated forms of Nav1.7 had normal resting currents, but
unlike cells transfected with wild-type Nav1.7, did not respond to
depolarization. These data suggest that action potentials that
communicate pain information are not generated in affected individuals.

Fertleman et al. identified SCN9A by positional cloning and haplotype
analysis as the gene involved in paroxysmal extreme pain disorder
(PEPD), which causes burning pain in ocular, mandibular and rectal
regions. In eight of the thirteen families examined, affected
individuals were heterozygous for one of eight SCN9A mutations. All
of the mutations were 'missense' mutations, replacing one amino acid
for another, and were located in the inactivation domain or regions
that interact with the inactivation domain of Nav1.7.

Cells expressing Nav1.7 mutants had prolonged sodium currents
relative to cells expressing wild-type Nav1.7, suggesting persistent
activity of DRG neurons in people with PEPD. However, carbamazepine,
an anti-epileptic drug that is effective in some people with PEPD,
reduced persistent current in cells expressing a Nav1.7 mutant,
suggesting that it relieves PEPD by restoring Nav1.7 inactivation.

According to Cox et al., SCN9A polymorphisms may cause population-
wide variations in pain threshold. Because people with nonfunctional
Nav1.7 lacked pain sensation but were otherwise normal, Nav1.7
inhibitors might relieve pain without causing side effects.

Debra Speert
Cox, J. J. et al. An SCN9A channelopathy causes congenital inability
to experience pain. Nature 444, 894–898 (2006).
Fertleman, C. R. et al. SCN9A mutations in paroxysmal extreme pain
disorder: Allelic variants underlie distinct channel defects and
phenotypes. Neuron 52, 767–774 (2006).

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