The role of peripheral T-type calcium channels in pain transmission
Introduction
Pain is usually a result of tissue injury in peripheral receptive fields of sensory neurons. Electrical signals generated at these sites are commonly amplified and transmitted further to the higher centers in the central nervous system (CNS) in order to generate a systemic response aimed at self-preservation. Damage to pain-sensing neural elements in sensory pathways (nociceptors) may result in a diminished ability to sense pain, or in contrast may lead to spontaneous pain and increased pain sensitivity [1], [2]. While it is known that neuronal excitability as a general measure of nociceptors’ activity may be modulated by a number of different voltage-gated ion channels, the precise cellular mechanism(s) underlying the nociceptive process are not well understood. Recent in vivo and in vitro studies have identified a novel role for low-voltage-activated (LVA) T-type calcium channels in sensory transmission and pain perception (nociception) in particular. In this review, we will summarize the most recent evidence relating T-type calcium channels in peripheral sensory neurons to pain processing under physiological conditions (e.g. acute nociceptive pain) and to pain processing under pathological conditions (e.g. neuropathic pain) (Fig. 1).
Section snippets
Early studies
The existence of LVA or T-type calcium conductance, which is the basis for low-threshold calcium spikes (LTS) in CNS, was suggested in the early 1980s with current-clamp studies using brain slice preparation [3], [4]. The first precise biophysical description of LVA Ca2+ channels using patch-clamp recordings was subsequently done by Carbone and Lux [5], [6] in in vitro preparation of chick and rat sensory (DRG) neurons. Several other groups [7], [8], [9] further clarified properties of LVA Ca2+
Redox modulation
Although numerous studies over the last three decades have shown that the function of HVA calcium channels in sensory neurons may be altered by a variety of endogenous pain modulators [20], a strong causative link between the modulation of T-type channels in peripheral nociceptors and pain transmission was not established until recently. In 2001, we reported that the reducing agents, dithiothreitol (DTT, a synthetic compound) and l-cysteine (an endogenous thiol-containing amino acid)
T-type channels and neuropathic pain
Our initial in vivo studies of acute peripheral thermal and mechanical nociception focused on redox- and/or neuroactive steroid-mediated modulation of T-type channels function suggested that these channels play an important role in pain perception in intact animals. To better understand the potential importance of T channels in chronic pain states, such as neuropathic pain (NPP), we examined the effects of locally injected redox agents, with or without a T-type channel blocker, mibefradil using
T-type Ca2+ channels in peripheral nociceptors: current status and future directions
T-type channels play a crucial role in the excitability of many neuronal systems and recently obtained data support the idea that they are boosters in the peripheral sensory pathway in general and nociception in particular. However, despite the presence of these channels in sensory neurons, their role in sensory information processing, including nociception, is not well understood. Nevertheless, based on presently available in vitro and in vivo studies, there is solid pharmacological,
Acknowledgments
Supported by NIH/NIDA KO8 awards DA00428 (S.M.T.) and DA00406 (V.J.-T.), NIH grants AG11355 (to V.J.-T), HD 44517 (to V.J.-T.) and GM 070726 (to S.M.T.). V.J.-T. is an established Investigator of the American Heart Association. We thank Michael Nelson for technical assistance.
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