Calcium signalling through L-type calcium channels: role in pathophysiology of spinal nociceptive transmission.
British Journal of Pharmacology. 2017-03-24; 175(12): 2362-2374
DOI: 10.1111/bph.13747
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L-type voltage-gated calcium channels are ubiquitous channels in the CNS. L-type
calcium channels (LTCs) are mostly post-synaptic channels regulating neuronal
firing and gene expression. They play a role in important physio-pathological
processes such as learning and memory, Parkinson’s disease, autism and, as
recognized more recently, in the pathophysiology of pain processes. Classically,
the fundamental role of these channels in cardiovascular functions has limited
the use of classical molecules to treat LTC-dependent disorders. However, when
applied locally in the dorsal horn of the spinal cord, the three families of LTC
pharmacological blockers – dihydropyridines (nifedipine), phenylalkylamines
(verapamil) and benzothiazepines (diltiazem) – proved effective in altering
short-term sensitization to pain, inflammation-induced hyperexcitability and
neuropathy-induced allodynia. Two subtypes of LTCs, Cav 1.2 and Cav 1.3, are
expressed in the dorsal horn of the spinal cord, where Cav 1.2 channels are
localized mostly in the soma and proximal dendritic shafts, and Cav 1.3 channels
are more distally located in the somato-dendritic compartment. Together with
their different kinetics and pharmacological properties, this spatial
distribution contributes to their separate roles in shaping short- and long-term
sensitization to pain. Cav 1.3 channels sustain the expression of plateau
potentials, an input/output amplification phenomenon that contributes to
short-term sensitization to pain such as prolonged after-discharges, dynamic
receptive fields and windup. The Cav 1.2 channels support calcium influx that is
crucial for the excitation-transcription coupling underlying nerve injury-induced
dorsal horn hyperexcitability. These subtype-specific cellular mechanisms may
have different consequences in the development and/or the maintenance of
pathological pain. Recent progress in developing more specific compounds for each
subunit will offer new opportunities to modulate LTCs for the treatment of
pathological pain with reduced side-effects.LINKED ARTICLES: This article is part
of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic
Pain. To view the other articles in this section visit
http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.