Targeting Ca channels to treat pain: T-type versus N-type

Altier, Christophe; Zamponi, Gerald W.

doi:10.1016/j.tips.2004.07.004

Cited by 133 publications

(100 citation statements)

References 59 publications

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“…Increasing evidence indicates that T-type channels play a key role in the control of nociceptive signaling [43]. LVA channels are highly expressed in mammalian sensory neurons [1,3,44,45] and up-regulation of their current by endogenous l-cysteine induces thermal hyperalgesia in animal models of neuropathic pain [46].…”

Section: T-type Channels Regulate the Frequency Of Mepscs In Nociceptmentioning

confidence: 99%

A new role for T-type channels in fast “low-threshold” exocytosis

et al. 2006

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Section: T-type Channels Regulate the Frequency Of Mepscs In Nociceptmentioning

confidence: 99%

A new role for T-type channels in fast “low-threshold” exocytosis

et al. 2006

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“…Increasing evidence indicates that T-type channels play a key role in the control of nociceptive signaling [1]. LVA channels are highly expressed in mammalian sensory neurons [13,22,59], and upregulation of their current by reducing agents like DTT or endogenous L-cysteine induces thermal hyperalgesia in animal models of neuropathic pain [64].…”

Section: T-type Channels Regulate the Frequency Of Mepscs In Nociceptmentioning

confidence: 99%

“…This is particularly true for the generation of LTS, oscillatory cell activity, and hormone secretion in cells lacking a vesicular apparatus. The critical role of T-type channels on important physiological functions is strengthened by the fact that either recruitment, overexpression, or malfunctioning of these channels is reported in a number of pathologies, including cardiac hypertrophy [65], hypertension [43], heart failure [16], absence epilepsy [68], neurogenic pain [1], and Parkinson's disease [73]. Most recently, T-type channels are shown to control the vesicular release of neurotransmitters in neurons and neuroendocrine cells [42,51], and very recent data indicate that LVA channels are involved in fast catecholamine release in adrenal chromaffin cells [9,25].…”

Section: Introductionmentioning

confidence: 99%

T-type channels-secretion coupling: evidence for a fast low-threshold exocytosis

Carbone¹,

Marcantoni²,

Giancippoli³

et al. 2006

Pflugers Arch - Eur J Physiol

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T-type channels are transient low-voltage-activated (LVA) Ca 2+ channels that control Ca 2+ entry in excitable cells during small depolarizations around resting potential. Studies in the past 20 years focused on the biophysical, physiological, and molecular characterization of T-type channels in most tissues. This led to a welldefined picture of the functional role of LVA channels in controlling low-threshold spikes, oscillatory cell activity, muscle contraction, hormone release, cell growth and differentiation. So far, little attention has been devoted to the role of T-type channels in transmitter release, which mainly involves channel types belonging to the highvoltage-activated (HVA) Ca 2+ channel family. However, evidence is accumulating in favor of a unique participation of T-type channels in fast transmitter release. Clear data are now reported in reciprocal synapses of the retina and olfactory bulb, synaptic contacts between primary afferent and second order nociceptive neurons, rhythmic inhibitory interneurons of invertebrates and clonal cell lines transfected with recombinant α 1 channel subunits. T-type channels also regulate the large dense-core vesicle release of neuroendocrine cells where Ca 2+ dependence, rate of vesicle release, and size of readily releasable pool appear comparable to those associated to HVA channels. This suggests that when sufficiently expressed and properly located near the release zones, T-type channels can trigger fast low-threshold secretion. In this study, we will review the main findings that assign a specific task to T-type channels in fast exocytosis, discussing their possible involvement in the control of the Ca 2+ -dependent processes regulating exocytosis like vesicle depletion and vesicle recycling.

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“…10,[15][16][17][18][19] Ziconotide produces antinociception in tissue-and nerve-injured animal models and in clinical situations, whereas it has little effect on acute physiological pain. However, ziconotide must be intrathecally injected to be efficacious and can induce undesirable side-effects.…”

Section: 237-41)mentioning

confidence: 99%

“…[11][12][13][14] N-type VDCCs are thus an important drug target for treatment of chronic pain. 10,[15][16][17][18][19] However, ziconotide must be intrathecally injected to be efficacious and can induce undesirable side-effects. 20,21) Current efforts have been focused on development of orally efficacious N-type VDCC blockers with better safety profile.…”

mentioning

confidence: 99%

Suppression of Formalin-Induced Nociception by Cilnidipine, a Voltage-Dependent Calcium Channel Blocker

Koganei

Shoji

Iwata

2009

Biological & Pharmaceutical Bulletin

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Cilnidipine is a 1,4-dihydropyridine-derived voltage-dependent calcium channel (VDCC) blocker and suppresses N-type VDCC currents in addition to L-type VDCC currents. An earlier investigation has suggested that intrathecally injected cilnidipine produces antinociception by blocking N-type VDCCs in mice. The present study using the rat formalin model examined antinociceptive effects of intrathecally and orally administered cilnidipine to elucidate a putative site of antinociception of cilnidipine, assess the efficacy of oral cilnidipine for pain relief, and clarify the mechanism(s) responsible for the antinociceptive effect of oral cilnidipine. Cilnidipine (whether intrathecal or oral) suppressed nociception in phases 1 and 2 of the formalin model. In addition, the potency of oral cilnidipine to suppress formalin-induced nociception in phase 2 was greater than that of oral gabapentin, a clinically available drug for treatment of neuropathic pain. Cilnidipine elicited antinociceptive effects without neurological side-effects including serpentine-like tail movement, whole body shaking, and allodynia. Such side-effects can be induced by higher doses of intrathecal ziconotide, a clinically available N-type VDCC blocker. In contrast, orally administered nifedipine, an L-type VDCC blocker, had no effect on either phase of formalin-induced nociception. These results suggest that cilnidipine acts on the spinal cord to produce antinociception and is efficacious for pain relief after oral administration with better safety profile than that of ziconotide. Furthermore, the failure of orally administered nifedipine to affect formalin-induced nociception raises the possibility that oral cilnidipine produces antinociception through, at least in part, spinal N-type VDCC blockade.

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Targeting Ca channels to treat pain: T-type versus N-type

Cited by 133 publications

References 59 publications

A new role for T-type channels in fast “low-threshold” exocytosis

A new role for T-type channels in fast “low-threshold” exocytosis

T-type channels-secretion coupling: evidence for a fast low-threshold exocytosis

Suppression of Formalin-Induced Nociception by Cilnidipine, a Voltage-Dependent Calcium Channel Blocker

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