State-dependent properties of a new T-type calcium channel blocker enhance CaV3.2 selectivity and support analgesic effects
TL;DR: The results suggest that the high potency of TTA‐A2 in the depolarized state strengthen its analgesic efficacy and selectivity toward pathological pain syndromes.
Abstract: T-type calcium channels encoded by the Ca(V)3.2 isoform are expressed in nociceptive primary afferent neurons where they contribute to hyperalgesia and thus are considered as a potential therapeutic target to treat pathological pain. Here we report that the small organic state-dependent T-type channel antagonist TTA-A2 efficiently inhibits recombinant and native Ca(V)3.2 currents. Although TTA-A2 is a pan Ca(V)3 blocker, it demonstrates a higher potency for Ca(V)3.2 compared to Ca(V)3.1. TTA-A2 selectivity for T-type currents was demonstrated in sensory neurons where it lowered cell excitability uniquely on neurons expressing T-type channels. In vivo pharmacology in Ca(V)3.2 knockout and wild type mice reveal that TTA-A2-mediated antinociception critically depends on Ca(V)3.2 expression. The pathophysiology of irritable bowel syndrome (IBS) was recently demonstrated to involve Ca(V)3.2 in a rat model of this disease. Oral administration of TTA-A2 produced a dose-dependent reduction of hypersensitivity in an IBS model, demonstrating its therapeutic potential for the treatment of pathological pain. Overall, our results suggest that the high potency of TTA-A2 in the depolarized state strengthen its analgesic efficacy and selectivity toward pathological pain syndromes. This characteristic would be beneficial for the development of analgesics targeting T-type channels, in particular for the treatment of pain associated with IBS.
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TL;DR: This review describes how use-dependent blockers of the different isoforms could selectively block calcium channels in particular pathologies, such as nociceptive neurons in pain states or in epileptic brain circuits, and describes how selectivity for different subtypes of calcium channels may be achieved in the future.
Abstract: Voltage-gated calcium channels are required for many key functions in the body. In this review, the different subtypes of voltage-gated calcium channels are described and their physiologic roles and pharmacology are outlined. We describe the current uses of drugs interacting with the different calcium channel subtypes and subunits, as well as specific areas in which there is strong potential for future drug development. Current therapeutic agents include drugs targeting L-type Ca(V)1.2 calcium channels, particularly 1,4-dihydropyridines, which are widely used in the treatment of hypertension. T-type (Ca(V)3) channels are a target of ethosuximide, widely used in absence epilepsy. The auxiliary subunit α2δ-1 is the therapeutic target of the gabapentinoid drugs, which are of value in certain epilepsies and chronic neuropathic pain. The limited use of intrathecal ziconotide, a peptide blocker of N-type (Ca(V)2.2) calcium channels, as a treatment of intractable pain, gives an indication that these channels represent excellent drug targets for various pain conditions. We describe how selectivity for different subtypes of calcium channels (e.g., Ca(V)1.2 and Ca(V)1.3 L-type channels) may be achieved in the future by exploiting differences between channel isoforms in terms of sequence and biophysical properties, variation in splicing in different target tissues, and differences in the properties of the target tissues themselves in terms of membrane potential or firing frequency. Thus, use-dependent blockers of the different isoforms could selectively block calcium channels in particular pathologies, such as nociceptive neurons in pain states or in epileptic brain circuits. Of important future potential are selective Ca(V)1.3 blockers for neuropsychiatric diseases, neuroprotection in Parkinson's disease, and resistant hypertension. In addition, selective or nonselective T-type channel blockers are considered potential therapeutic targets in epilepsy, pain, obesity, sleep, and anxiety. Use-dependent N-type calcium channel blockers are likely to be of therapeutic use in chronic pain conditions. Thus, more selective calcium channel blockers hold promise for therapeutic intervention.
762 citations
Cites background from "State-dependent properties of a new..."
...2 channels pharmacologically thus mediates analgesia (François et al., 2014)....
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TL;DR: An overview of recent advances on sodium, calcium, potassium and chloride channels that are emerging as especially attractive targets for the treatment of pain is given.
Abstract: The transmission and processing of pain signals relies critically on the activities of ion channels that are expressed in afferent pain fibers. This includes voltage-gated channels, as well as background (or leak) channels that collectively regulate resting membrane potential and action potential firing properties. Dysregulated ion channel expression in response to nerve injury and inflammation results in enhanced neuronal excitability that underlies chronic neuropathic and inflammatory pain. Pharmacological modulators of ion channels, particularly those that target channels on peripheral neurons, are being pursued as possible analgesics. Over the past few years, a number of different types of ion channels have been implicated in afferent pain signaling. Here we give an overview of recent advances on sodium, calcium, potassium and chloride channels that are emerging as especially attractive targets for the treatment of pain.
340 citations
TL;DR: A broad overview of different calcium-permeable ion channels in the afferent pain pathway and their role in pain pathophysiology is provided.
Abstract: The detection and processing of painful stimuli in afferent sensory neurons is critically dependent on a wide range of different types of voltage- and ligand-gated ion channels, including sodium, calcium, and TRP channels, to name a few. The functions of these channels include the detection of mechanical and chemical insults, the generation of action potentials and regulation of neuronal firing patterns, the initiation of neurotransmitter release at dorsal horn synapses, and the ensuing activation of spinal cord neurons that project to pain centers in the brain. Long-term changes in ion channel expression and function are thought to contribute to chronic pain states. Many of the channels involved in the afferent pain pathway are permeable to calcium ions, suggesting a role in cell signaling beyond the mere generation of electrical activity. In this article, we provide a broad overview of different calcium-permeable ion channels in the afferent pain pathway and their role in pain pathophysiology.
261 citations
Cites background from "State-dependent properties of a new..."
...Indeed, new generation state-dependent blockers such as TTA-P2 and TTA-A2, which appear to interact preferentially with inactivated T-type calcium channels, both elicit analgesia in rodent models of pain (172, 303)....
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TL;DR: Recent advances in the understanding of the neurobiology of pain are beginning to offer opportunities for developing novel therapeutic strategies and revisiting existing targets, including modulating ion channels, enzymes and G-protein-coupled receptors.
Abstract: Acute and chronic pain complaints, although common, are generally poorly served by existing therapies. This unmet clinical need reflects a failure to develop novel classes of analgesics with superior efficacy, diminished adverse effects and a lower abuse liability than those currently available. Reasons for this include the heterogeneity of clinical pain conditions, the complexity and diversity of underlying pathophysiological mechanisms, and the unreliability of some preclinical pain models. However, recent advances in our understanding of the neurobiology of pain are beginning to offer opportunities for developing novel therapeutic strategies and revisiting existing targets, including modulating ion channels, enzymes and G-protein-coupled receptors.
232 citations
TL;DR: Voltage-gated calcium channel classification—genes and proteins and genetic analysis of neuropsychiatric syndromes of psychiatric disorders and their sequelae.
199 citations
Cites background from "State-dependent properties of a new..."
...In contrast, TTA-A2 and TTA-P2 are selective CaV3 blockers (Choe et al., 2011; Francois et al., 2013), which are of use in defining the physiological roles of T-type channels....
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...CaV3 blockers (Choe et al., 2011; Francois et al., 2013), which are of use in defining the physiological roles of T-type channels....
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References
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TL;DR: The Committee for Research and Ethical Issues of the International Association for the Study of Pain (IASP®) is concerned with the ethical aspects of studies producing experimental pain and any suffering it may cause in animals.
Abstract: The Committee for Research and Ethical Issues of the International Association for the Study of Pain (IASP®) is concerned with the ethical aspects of studies producing experimental pain and any suffering it may cause in animals. Such studies are essential if new and clinically relevant knowledge about the mechanisms of pain is to be acquired. Investigations in conscious animals intended to stimulate chronic pain in man are being performed. Such experiments require careful planning to avoid or at least minimize pain in the animals.
7,443 citations
"State-dependent properties of a new..." refers methods in this paper
...Pain threshold was considered to be reached for 2 withdrawals out of 5 consecutive filament applications....
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...Experiments were performed according to the recommendations of the International Association for the Study of Pain [49], and approved by the local ethical committee....
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...Complete for the Study of Pain....
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...2012 International Association for the Study of Pain....
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...Supported in part by Grants from the ANR (ANR-09-MNPS-037, ANR-08-NMPS-025), the Institut UPSA de la Douleur, and the AFM (AFM-12-PainT)....
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TL;DR: The goal of this review is to provide a comprehensive description of T-type currents, their distribution, regulation, pharmacology, and cloning.
Abstract: T-type Ca2+ channels were originally called low-voltage-activated (LVA) channels because they can be activated by small depolarizations of the plasma membrane. In many neurons Ca2+ influx through L...
1,620 citations
"State-dependent properties of a new..." refers background in this paper
...In addition, TTA-A2 effect was investigated on the generation of LTCP after a 2-s-long hyperpolarizing step that directly relies on T-type channel expression [14,26,37]....
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...These channels open in response to weak depolarizations from the membrane potential and therefore regulate excitability [7,37]....
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...Second, TTA-A2 suppresses rebound excitability after hyperpolarization that relies on T-type channels [37]....
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TL;DR: In this paper, localized central and peripheral nervous system expression of three transcripts (α1G, α1H, and α1I) of the T-type calcium channel family (CaVT) was found.
Abstract: Low voltage-activated (T-type) calcium currents are observed in many central and peripheral neurons and display distinct physiological and functional properties. Using in situ hybridization, we have localized central and peripheral nervous system expression of three transcripts (α1G, α1H, and α1I) of the T-type calcium channel family (CaVT). Each mRNA demonstrated a unique distribution, and expression of the three genes was largely complementary. We found high levels of expression of these transcripts in regions associated with prominent T-type currents, including inferior olivary and thalamic relay neurons (which expressed α1G), sensory ganglia, pituitary, and dentate gyrus granule neurons (α1H), and thalamic reticular neurons (α1I and α1H). Other regions of high expression included the Purkinje cell layer of the cerebellum, the bed nucleus of the stria terminalis, the claustrum (α1G), the olfactory tubercles (α1H and α1I), and the subthalamic nucleus (α1I and α1G). Some neurons expressed high levels of all three genes, including hippocampal pyramidal neurons and olfactory granule cells. Many brain regions showed a predominance of labeling for α1G, including the amygdala, cerebral cortex, rostral hypothalamus, brainstem, and spinal cord. Exceptions included the basal ganglia, which showed more prominent labeling for α1H and α1I, and the olfactory bulb, the hippocampus, and the caudal hypothalamus, which showed more even levels of all three transcripts. Our results are consistent with the hypothesis that differential gene expression underlies pharmacological and physiological heterogeneity observed in neuronal T-type calcium currents, and they provide a molecular basis for the study of T-type channels in particular neurons.
741 citations
TL;DR: This review concentrates on the antiarrhythmic drug literature pertinent to an evaluation of the modulated receptor hypothesis: lidocaine, procainamide, quinidine, diphenylhydantoin, and propranolol.
Abstract: At the time of the last review of antiarrhythmic drugs in this series in 1 975 (1) , the important developments in the field centered around the "classical" agents: lidocaine, procainamide, quinidine, diphenylhydantoin (now phenytoin), and propranolol. That review properly emphasized the importance of new informa tion regarding the effects of these agents on diseased tissue (e.g. obtained from infarcted hearts) or on normal tissue stressed in the muscle chamber (e.g. by depolarization with potassium). However, data and concepts available at that time were not sufficient to explain the important differences among the effects of these drugs on different types of cardiac tissue, or the difference in sensitiv ity of diseased and depolarized tissue as compared to normal tissue. Since 1 975, a modest revolution in antiarrhythmic drug development, re search, and clinical application has occurred. The number of agents in active clinical use or investigation in the U.S. is now more than 18 (2, 3). In addition, a major new class of agents, the calcium channel blockers, has come into general use (4, 5) . Furthermore, an attempt has been made to extend our understanding of the mechanism of action at the molecular level: the modulated receptor hypothesis (6, 7). This review concentrates on the antiarrhythmic drug literature pertinent to an evaluation of the modulated receptor hypothesis. A number of general reviews
563 citations
"State-dependent properties of a new..." refers background in this paper
...The concept of state-dependent effect of a drug on ion channels has been described for a long time for sodium and calcium channels [17]....
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TL;DR: The results provide direct evidence linking CaV3.2 T‐type channels to pain perception and suggest that CaV 3.2 may offer a specific molecular target for the treatment of pain.
Abstract: Analgesic therapies are still limited and sometimes poorly effective, therefore finding new targets for the development of innovative drugs is urgently needed. In order to validate the potential utility of blocking T-type calcium channels to reduce nociception, we explored the effects of intrathecally administered oligodeoxynucleotide antisenses, specific to the recently identified T-type calcium channel family (CaV3.1, CaV3.2, and CaV3.3), on reactions to noxious stimuli in healthy and mononeuropathic rats. Our results demonstrate that the antisense targeting CaV3.2 induced a knockdown of the CaV3.2 mRNA and protein expression as well as a large reduction of 'CaV3.2-like' T-type currents in nociceptive dorsal root ganglion neurons. Concomitantly, the antisense treatment resulted in major antinociceptive, anti-hyperalgesic, and anti-allodynic effects, suggesting that CaV3.2 plays a major pronociceptive role in acute and chronic pain states. Taken together, the results provide direct evidence linking CaV3.2 T-type channels to pain perception and suggest that CaV3.2 may offer a specific molecular target for the treatment of pain.
443 citations
"State-dependent properties of a new..." refers background or methods in this paper
...After the identification of the CaV3 genes, genetic elimination of T-type isoforms has been possible by targeted antisense [6,26,30] and gene knockout (KO) approaches [9,12,31]....
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...2 transcript and protein in these neurons [6,26,40,42]....
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...2 channels in somatic neuropathic pain of distinct etiologies including traumatic nerve injuries [6,19,41], metabolic disorders such as diabetes [20,30], and toxic chemotherapies [35]....
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...In order to corroborate recombinant and native channel pharmacology, whole cell calcium currents were recorded from medium sized dissociated mouse DRG neurons expressing low voltage–activated T-type currents of large amplitude as well as high-voltage-activated (HVA) currents [6,15,33]....
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...2-like properties including the pharmacological inhibition by low concentrations of nickel ions [2,6,9,26,34,47], corroborating the prevalent expression of the CaV3....
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