The rapid entry of
calcium into cells through activation of voltage-gated
calcium channels directly affects membrane potential and contributes to electrical excitability, repetitive firing patterns, excitation-contraction coupling, and gene expression. At presynaptic nerve terminals,
calcium entry is the initial trigger mediating the release of
neurotransmitters via the
calcium-dependent fusion of synaptic vesicles and involves interactions with the
soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex of synaptic release
proteins. Physiological factors or drugs that affect either presynaptic
calcium channel activity or the efficacy of
calcium-dependent vesicle fusion have dramatic consequences on synaptic transmission, including that mediating
pain signaling. The
N-type calcium channel exhibits a number of characteristics that make it an attractive target for therapeutic intervention concerning chronic and
neuropathic pain conditions. Within the past year, both U.S. and European regulatory agencies have approved the use of the cationic
peptide Prialt for the treatment of
intractable pain.
Prialt is the first
N-type calcium channel blocker approved for clinical use and represents the first new proven mechanism of action for
chronic pain intervention in many years. The present review discusses the rationale behind targeting the
N-type calcium channel, some of the limitations confronting the widespread clinical application of
Prialt, and outlines possible strategies to improve upon
Prialt's relatively narrow therapeutic window.