The role of peripheral T-type calcium channels in pain transmission

doi:10.1016/j.ceca.2006.04.024

Cell Calcium

Volume 40, Issue 2, August 2006, Pages 197-203

https://doi.org/10.1016/j.ceca.2006.04.024 Get rights and content

Abstract

Some of the earliest detailed descriptions of biophysical properties of low voltage-activated (LVA) or transient (T) type Ca²⁺ channels were done using in vitro preparation of primary sensory or dorsal root ganglion (DRG) neurons that are known for their functional role in processing pain signals. However, in spite of these early discoveries, T-type channels were not implicated in sensory transmission in general and pain processing (nociception) in particular until recently. New evidence obtained using an array of techniques such as electrophysiological recordings, pharmacological behavioral experiments as well as molecular techniques strongly supports the role of peripheral T-type Ca²⁺ channels in boosting nociceptive transmission in a variety of experimental pain models. Therefore, these channels in peripheral sensory neurons may be the important, although previously unappreciated, targets for novel pain therapies. In this article, we review past, present and future findings aimed at illuminating the role of peripheral T-type Ca²⁺ channels in nociception and the value of these channels as cellular targets for potential drug developments.

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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Thalamic T-type currents are enhanced in several rodent models of absence epilepsy; correspondingly, several gain-of-function mutations within CACNA1 genes are associated with human epilepsies, whereas T-type channel blockers have been shown to suppress seizures and are efficacious in treatment of absent seizures in humans (for a review, see Refs. 4, 8). In the peripheral nervous system, T-type Ca2+ channels (and Cav3.2 in particular) are abundant in small-diameter, capsaicin-sensitive (presumably nociceptive) dorsal root ganglion neurons (9–12), as well as in two distinct types of low-threshold mechanoreceptors innervating skin hair follicles (13). The discovery of a relatively high abundance of T-type Ca2+ channels in nociceptors led to establishment of the prominent role of these channels in peripheral nociceptive transmission.
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The role of peripheral T-type calcium channels in pain transmission

Abstract

Introduction

Section snippets

Early studies

Redox modulation

T-type channels and neuropathic pain

T-type Ca2+ channels in peripheral nociceptors: current status and future directions

Acknowledgments

Pain

Biophys. J.

Curr. Opin. Neurobiol.

Neuron

Neuron

Biochem. Biophys. Res. Commun.

Brain Res.

Pain

Pain

Pain

Pain

Brain Res.

Peptides and the primary afferent nociceptor

J. Neurosci.

Electrophysiology of mammalian inferior olivary neurones in vitro. Different types of voltage-dependent ionic conductances

J. Physiol. (Lond.)

Properties and distribution of ionic conductances generating electroresponsiveness of mammalian inferior olivary neurones in vitro

J. Physiol. (Lond.)

A low-voltage activated, fully inactivating Ca2+ channel in vertebrate sensory neurons

Nature

Two types of calcium channels in the somatic membrane of new-born rat dorsal root ganglion neurons

J. Physiol. (Lond.)

Single-channel recordings of three types of calcium channels in chick sensory neurones

J. Physiol. (Lond.)

Depolarization elicits two distinct calcium currents in vertebrate sensory neurons

Pflugers. Arch.

Transient low-threshold Ca2+ current triggers burst firing through an after-depolarizing potential in an adult mammalian neuron

Proc. Natl. Acad. Sci. U.S.A.

The intrinsic electrophysiological properties of mammalian neurons: insight into central nervous system function

Sci. DC Wash.

Calcium current variation between acutely isolated rat dorsal root ganglion neurons of different size

J. Physiol. (Lond.)

T-type calcium channels: heterogeneous expression in rat sensory neurons and selective modulation by phorbol esters

J. Neurosci.

Conduction velocity is related to morphological cell type in rat dorsal root ganglion neurons

J. Physiol. (Lond.)

T-type Ca²⁺ channels in peripheral nociceptors: current status and future directions

A low-voltage activated, fully inactivating Ca²⁺ channel in vertebrate sensory neurons

Transient low-threshold Ca²⁺ current triggers burst firing through an after-depolarizing potential in an adult mammalian neuron