Role of voltage-gated calcium channels in ascending pain pathways

Abstract

Voltage gated calcium channels (VGCCs) are well established mediators of pain signals in primary afferent neurons. N-type calcium channels are localized to synaptic nerve terminals in laminae 1 and 2 of the dorsal horn where their opening results in the release of neurotransmitters such as glutamate and substance P. The contribution of N-type channels to the processing of pain signals is regulated by alternate splicing of the N-type channel gene, with unique N-type channel splice variants being expressed in small nociceptive neurons. In contrast, T-type VGCCs of the Ca(v)3.2 subtype are likely localized to nerve endings where they regulate cellular excitability. Consequently, inhibition of N-type and Ca(v)3.2 T-type VGCCs has the propensity to mediate analgesia. T-type channel activity is regulated by redox modulation, and can be inhibited by a novel class of small organic blockers. N-type VGCC activity can be potently inhibited by highly selective peptide toxins that are delivered intrathecally, and the search for small organic blockers with clinical efficacy is ongoing. Here, we provide a brief overview of recent advances in this area, as presented at the Spring Pain Research conference (Grand Cayman, 2008).

Fig. 1

N-type and T-type calcium channels in the primary afferent signaling pathway. High voltage-activated N-type channels are highly localized to presynaptic terminals in laminae I and II of the dorsal horn. Action potentials carried along dorsal root ganglion cells (mainly C- and Aδ-afferents) trigger the opening of pre-synaptic N-type calcium channels which in turn initiate the release of nociceptive transmitters such as glutamate, substance P and CGRP onto spinal interneurons and projection neurons. Low voltage-activated T-type calcium channels are primarily localized more upstream in the pathway and are thought to be both involved in generating sensory potentials out near free nerve endings, as well as being present in DRG cell bodies where they likely contribute to the generation and frequency of action potentials. Modified from Hildebrand and Snutch, 2006; Schaible and Richter, 2004.