Biomedical Engineering Reference
In-Depth Information
and regulation of vital systems, such as circulation. Under normal physiological
conditions, ion channels permit the orderly movement of ions across both plasma
and intracellular cell membranes. A number of disease states as well as cell death also
occur under pathologic conditions in which the disorderly movement of ions through
these channels dominates. The aberrant elevation of intracellular Ca
2+
levels through
altered Ca
2+
channel function is related to a variety of serious human pathophysiologi-
cal conditions, including cardiovascular diseases, muscle disorders, acute or chronic
pain, epilepsy, cerebellar ataxia, migraine, mood disorders, and certain types of cancer
[
18
]. Nowycky et al. by studying the Ca
2+
current in dorsal root ganglion (DRG)
neurons gave the functional identification of NCC for the first time and its use in pain
research. The drug toward blocking this target further took 20 years by the discovery
of Priat by USA and Europe for the treatment of chronic pain [
19
].
NCC is located predominantly in neurons and is associated with a variety of
neuronal responses, including neurodegeneration. Experimental autoimmune enceph-
alomyelitis study in mice by Tokuhara et al. recently concluded the role of NCC in
mice neurodegeneration [
20
]. This channel role in cardiovascular disease was also
well known [
21
]. Neuropathic pain behavioral models in animal showed that NCC
blockers when administered via spinal cord attenuates hyperalgesia and allodynia
(pain due to stimulus) by mechanical, chemical, and thermal way of stimulation [
22
].
Further, this Ca
2+
channel antagonist blockers are responsible for the hyperexcitability
of dorsal horn neurons and behavioral peripheral nerve damage (hyperalgesia) seen in
the animal models of inflammatory pain [
23
]. It was further established by Saegusa
et al. that NCC was a key target for continuous (persistent) pain by studying three
strains of
a
1B
gene knockout mice with elevated neural processes of encoding and
noxious stimuli caused due to tissue or nerve injury [
5
].
Recent studies show that a ubiquitous form of G-protein modulation involves an
inhibition of classical voltage-dependent regulation of mammalian Cav2.1 and Cav2.2
(NCC) channels [
24
]. VGCCs also affect the sensory neurons and many animals have
these neurons activated preferentially by stimuli with the potential to cause tissue
damage. In humans and other mammals, such sensory neurons are called nociceptors
and generate signals interpreted by the central nervous systemas pain. Thus, antagonist
binding to NCC decreases the pain related neurotransmitters leading to the suppression
of the signals causing neuropathic pain [
1
,
25
]. Further, capsaicin-sensitive dorsal root
ganglion (DRG) neurons express a unique Cav2.2 splicing form, raising the possibility
of developing drugs that preferentially target NCCs in primary afferent neurons. On the
contrary, it remains to be determined whether this splice variant is also expressed in
human DRG neurons and whether the encoded
a
1B
subunit is localized at primary
afferent neuron terminals, where they would regulate neurotransmission [
26
].
Furthermore, it is also possible to develop a use-dependent blocker that selec-
tively regulates the DRG-specific NCCs. Success in that endeavor should produce
an analgesic with an even better safety profile. An important concern, however, are
those DRG neurons also express the more ubiquitous form of
a
1B
subunits, in
addition to the specific variant. Which variant underlies synaptic transmission in the
setting of persistent pain remains to be determined. In any case, a more general use-
dependent blocker may be useful for alleviating pain as sympathetic postganglionic
neurotransmission is predominantly mediated through NCCs [
1
,
2
].
