Biomedical Engineering Reference
In-Depth Information
reducing excitability of inhibitory interneurons, thus inducing epileptic seizures.
Mutations in
SCN2A
, found in benign neonatal familial seizure, induce a mild
clinical condition and convulsions that disappear into adulthood, in agreement
with the transient expression of Na
v
1.2 in myelinated axons of excitatory neurons
early during postnatal development [
32
]. The related symptoms are generally
associated with a decrease in channel density in the membrane, leading to a lower
magnitude of whole-cell currents [
33
]. Mutations in
SCN1B
have been the first to be
associated with GEFS+ [
34
]. Mutated
1-subunits are characterized by a reduced
function, which impairs their modulation of
b
-subunits and probably decreases the
level of channel expression in the membrane [
23
,
24
,
34
].
a
2.4.2 Pain
The perception of pain is a physiological process, which contributes to the mainte-
nance of body integrity as it alerts to forthcoming harms. Nociception is the
physiological system that conveys somatic information along the pain cascade
from peripheral receptors to the spinal cord and to the brain, and can discriminate
potentially damaging from innocuous stimuli. Conscious awareness of such senso-
rial signaling results into pain. Nociception is encoded by action potentials and
specific VGSC subtypes are involved in their outset and propagation [
35
]. Abnor-
mal expression and/or functioning of VGSCs, typical of certain inherited
channelopathies, have been linked with inflammatory or neuropathic pain
[
35
-
37
]. In contrast to inflammatory or nociceptive pain, which is caused by actual
tissue damage or potentially tissue damaging stimuli, neuropathic pain is produced
either by damage to, or pathological change in, the PNS or CNS, the system that
normally signals pain. The key role of VGSCs in pain has been empirically
confirmed by symptomatic relief in patients treated with sodium channel blockers
[
38
,
39
], but the nonspecific nature and side effects of existing blockers have
limited their clinical utility. At least five subunits are expressed in human dorsal
root ganglion (DRG) neurons, Na
v
1.7, Na
v
1.8, Na
v
1.9, Na
v
1.1, and Na
v
1.3. Chronic
injury to sensory neurons triggers neuropathic pain possibly due to the upregulation
of embryonic Na
v
1.3 in the somata and of Na
v
1.8 in DRG neurons [
40
,
41
], to an
abnormal redistribution of Na
v
1.8 and Na
v
1.9 from the somata to the peripheral
axon at the site of the lesion, and to the upregulation of
b
3
subunits [
42
,
43
].
These changes induce spontaneous firing of nociceptive neurons at abnormally
elevated frequencies and from ectopic sites. Upregulation of Na
v
1.3 within sec-
ond-order spinal cord dorsal horn neurons and third-order thalamic neurons seem to
be involved in central neuropathic pain occurring after spinal cord injury. It is
possible that the abnormal functioning of the VGSC subunit makes the host neurons
hyperexcitable so that they act as pain amplifiers and generators [
44
]. There are
strong evidences that Na
v
1.7-1.9 contribute to inflammatory pain [
45
]. Na
v
1.7 has
recently gained particular interest in pain research as a genetic link has been found
between the VGSC subtype and certain hereditary pain disorders in humans. In
particular, dominant gain-of-function mutations in
SCN9A
, the gene that encodes
b
2
and
