Calcium Channels As Therapeutic Targets in Neuropathic Pain

Yaksh, Tony L.

doi:10.1016/j.jpain.2005.09.007

Cited by 135 publications

(93 citation statements)

References 223 publications

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“…In the central nervous system, these channels carry out a variety of actions, regulating activity-dependent gene expression, synaptic transmission and neuronal excitability. The VGCCs most extensively studied in nociception are the N-, P/Q-and T-type Ca 2+ channels [45][46][47]. It is well established that an increase in intracellular Ca 2+ has an important role in neurotransmitter release, cell membrane excitability, activation of intracellular proteins, and reduction of the pain threshold [48][49][50].…”

Section: Discussionmentioning

confidence: 99%

Role of pertussis toxin-sensitive G-protein, K+ channels, and voltage-gated Ca2+ channels in the antinociceptive effect of inosine

Macedo-Júnior

Nascimento

Luiz-Cerutti

et al. 2012

Purinergic Signalling

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Inosine is the first metabolite of adenosine. It exerts an antinociceptive effect by activating the adenosine A 1 and A 2A receptors. We have previously demonstrated that inosine exhibits antinociceptive properties in acute and chronic mice models of nociception. The aim of this study was to investigate the involvement of pertussis toxinsensitive G-protein-coupled receptors, as well as K + and Ca 2+ channels, in the antinociception promoted by inosine in the formalin test. Mice were pretreated with pertussis toxin (2.5 μg/site, i.t., an inactivator of G i/0 protein); after 7 days, they received inosine (10 mg/kg, i.p.) or morphine (2.5 mg/kg, s.c., used as positive control) immediately before the formalin test. Another group of animals received tetraethylammonium (TEA) or 4-aminopyridine (4-AP) (1 μg/site, i.t., a non-specific voltage-gated K + channel blockers), apamin (50 ng/site, i.t., a small conductance Ca 2+ -activated K + channel blocker), charybdotoxin (250 pg/site, i.t., a largeconductance Ca 2+ -activated K + channel blocker), glibenclamide (100 μg/site, i.t., an ATP-sensitive K + channel blocker) or CaCl 2 (200 nmol/site, i.t.). Afterwards, the mice received inosine (10 mg/kg, i.p.), diclofenac (10 mg/kg, i.p., a positive control), or morphine (2.5 mg/kg, s.c., a positive control) immediately before the formalin test. The antinociceptive effect of inosine was reversed by the pre-administration of pertussis toxin (2.5 μg/site, i.t.), TEA, 4-aminopyridine, charybdotoxin, glibenclamide, and CaCl 2 , but not apamin. Further, all K + channel blockers and CaCl 2 reversed the antinociception induced by diclofenac and morphine, respectively. Taken together, these data suggest that the antinociceptive effect of inosine is mediated, in part, by pertussis toxinsensitive G-protein coupled receptors and the subsequent activation of voltage gated K + channel, large conductance Ca 2+ -activated and ATP-sensitive K + channels or inactivation of voltage-gated Ca 2+ channels. Finally, small conductance Ca 2+ -activated K + channels are not involved in the antinociceptive effect of inosine.

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Section: Discussionmentioning

confidence: 99%

Role of pertussis toxin-sensitive G-protein, K+ channels, and voltage-gated Ca2+ channels in the antinociceptive effect of inosine

Macedo-Júnior

Nascimento

Luiz-Cerutti

et al. 2012

Purinergic Signalling

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“…N-type Ca 2+ channels are expressed mainly in the surface layer (laminae I and II) of the spinal dorsal horn and DRG and are involved in the release of neurotransmitters such as glutamate, CGRP, and substance P from the primary afferent nerve terminal (25). The protein expression of N-type Ca 2+ channel has been reported to be increased after a nerve injury in the DRG and the surface layer of the spinal dorsal horn (25).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…The protein expression of N-type Ca 2+ channel has been reported to be increased after a nerve injury in the DRG and the surface layer of the spinal dorsal horn (25). In addition, the expression of neuropathic pain was impaired in Ntype Ca 2+ channel-knock-out mice (25,26). In the postoperative pain model, ω-conotoxin MVIIA, an N-type Ca 2+ -channel blocker, but not other blockers (L-, T-, and P/Q-type Ca 2+ -channel blocker), significantly attenuated the post-incision induced allodynic response (8,27).…”

Section: Discussionmentioning

confidence: 99%

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Spinal Mechanism Underlying the Antiallodynic Effect of Gabapentin Studied in the Mouse Spinal Nerve Ligation Model

et al. 2012

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Abstract. We studied the antiallodynic effect of gabapentin (GBP) in the mouse model of neuropathic pain, aiming at clarifying the underlying mechanism. The L5 spinal nerve ligation induced tactile allodynia, an increase of CD11b expression, and an increase in the protein expression level of the voltage-dependent Ca 2+ channel α 2 /δ-1 subunit in the spinal dorsal horn on the injured side. The chronic intrathecal administration of GBP (100 μg/body per day) as well as ω-conotoxin MVIIA, an N-type Ca 2+ -channel blocker, completely suppressed allodynia, but did not attenuate the CD11b expression. The antiallodynic effect of GBP lasted for several days after the termination of the drug, while that of ω-conotoxin MVIIA disappeared immediately after the termination. GBP suppressed the elevation of the protein level of the α 2 /δ-1 subunit in the spinal dorsal horn, although it did not affect its mRNA level in the L5 DRG. These results suggest that GBP inhibits the development of allodynia by suppressing the up-regulation of N-type Ca 2+ channels, through normalization of the protein level of the α 2 /δ-1 subunit at the primary afferent nerve terminal via the inhibition of its anterograde transport. In addition, we propose that the nerve injury enhances the expression level of α 2 /δ-1 in the downstream of the activation of microglia.

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“…Various Ca 2+ channel blockers have been tested in the postoperative, inflammatory and neuropathic pain models . The potential use of Ca 2+ channel blockers for neuropathic pain treatment and roles of Ca 2+ channels in ascending pain pathway have been well reviewed (Yaksh, 2006;Zamponi et al, 2009). …”

Section: Voltage-gated Camentioning

confidence: 99%

Intrathecal Studies on Animal Pain Models

Cheng¹

2012

Pain Management - Current Issues and Opinions

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Calcium Channels As Therapeutic Targets in Neuropathic Pain

Cited by 135 publications

References 223 publications

Role of pertussis toxin-sensitive G-protein, K+ channels, and voltage-gated Ca2+ channels in the antinociceptive effect of inosine

Role of pertussis toxin-sensitive G-protein, K+ channels, and voltage-gated Ca2+ channels in the antinociceptive effect of inosine

Spinal Mechanism Underlying the Antiallodynic Effect of Gabapentin Studied in the Mouse Spinal Nerve Ligation Model

Intrathecal Studies on Animal Pain Models

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