Upregulation of the T-type calcium current in small rat sensory neurons after chronic constrictive injury of the sciatic nerve.
01 Jun 2008-Journal of Neurophysiology (American Physiological Society)-Vol. 99, Iss: 6, pp 3151-3156
TL;DR: The finding that T-type currents are upregulated in a CCI model of peripheral neuropathy and earlier pharmacological and molecular studies suggest that T -type channels may be potentially useful therapeutic targets for the treatment of neuropathic pain associated with partial mechanical injury to the sciatic nerve.
Abstract: Recent data indicate that peripheral T-type Ca2+ channels are instrumental in supporting acute pain transmission. However, the function of these channels in chronic pain processing is less clear. T...
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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 "Upregulation of the T-type calcium ..."
...2 that result in increased pain in humans have been reported in the literature, peripheral nerve injury or inflammation (Jagodic et al., 2008; García-Caballero et al., 2014), diabetes (Jagodic et al....
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...2 that result in increased pain in humans have been reported in the literature, peripheral nerve injury or inflammation (Jagodic et al., 2008; García-Caballero et al., 2014), diabetes (Jagodic et al., 2007; Messinger et al., 2009), and colonic inflammation (Marger et al., 2011a) all give rise to…...
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TL;DR: Attention is focused on salient aspects of voltage-gated calcium channel function, physiology, and pathophysiology that are of critical importance to brain function.
509 citations
Cites background from "Upregulation of the T-type calcium ..."
...4 channel mutations that lead to truncated channels (Jalkanen et al., 2006), suggesting that the Cava2d4 mutation may result in altered Cav1....
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TL;DR: The discovery of new bioactives using proteomic/transcriptomic approaches combined with high-throughput platforms and better defining conopeptide structure-activity relationships using relevant membrane protein crystal structures are expected to grow the already significant impact conopePTides have had as both research probes and leads to new therapies.
Abstract: Conopeptides are a diverse group of recently evolved venom peptides used for prey capture and/or defense. Each species of cone snails produces in excess of 1000 conopeptides, with those pharmacologically characterized (≈ 0.1%) targeting a diverse range of membrane proteins typically with high potency and specificity. The majority of conopeptides inhibit voltage- or ligand-gated ion channels, providing valuable research tools for the dissection of the role played by specific ion channels in excitable cells. It is noteworthy that many of these targets are found to be expressed in pain pathways, with several conopeptides having entered the clinic as potential treatments for pain [e.g., pyroglutamate1-MrIA (Xen2174)] and one now marketed for intrathecal treatment of severe pain [ziconotide (Prialt)]. This review discusses the diversity, pharmacology, structure-activity relationships, and therapeutic potential of cone snail venom peptide families acting at voltage-gated ion channels (ω-, μ-, μO-, δ-, ι-, and κ-conotoxins), ligand-gated ion channels (α-conotoxins, σ-conotoxin, ikot-ikot, and conantokins), G-protein-coupled receptors (ρ-conopeptides, conopressins, and contulakins), and neurotransmitter transporters (χ-conopeptides), with expanded discussion on the clinical potential of sodium and calcium channel inhibitors and α-conotoxins. Expanding the discovery of new bioactives using proteomic/transcriptomic approaches combined with high-throughput platforms and better defining conopeptide structure-activity relationships using relevant membrane protein crystal structures are expected to grow the already significant impact conopeptides have had as both research probes and leads to new therapies.
367 citations
Cites background from "Upregulation of the T-type calcium ..."
...In neuropathic pain models, T-type channel current density is up-regulated, and this contributes to sensory neuron hyperexcitability (Jagodic et al., 2007, 2008)....
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TL;DR: An overview of calcium channels as drug targets for nervous system disorders is provided, and potential challenges and opportunities for the development of new clinically effective calcium channel inhibitors are discussed.
Abstract: Voltage-gated calcium channels are important regulators of brain, heart and muscle functions, and their dysfunction can give rise to pathophysiological conditions ranging from cardiovascular disorders to neurological and psychiatric conditions such as epilepsy, pain and autism. In the nervous system, calcium channel blockers have been used successfully to treat absence seizures, and are emerging as potential therapeutic avenues for pathologies such as pain, Parkinson disease, addiction and anxiety. This Review provides an overview of calcium channels as drug targets for nervous system disorders, and discusses potential challenges and opportunities for the development of new clinically effective calcium channel inhibitors.
301 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 "Upregulation of the T-type calcium ..."
...On the flip side, T-type calcium channel activity is increased in afferent pain fibers in a number of chronic pain conditions, such as after spinal nerve injury (996), diabetic neuropathy (131, 427), and mechanical nerve injury (426, 938)....
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References
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TL;DR: A peripheral mononeuropathy was produced in adult rats by placing loosely constrictive ligatures around the common sciatic nerve and the postoperative behavior of these rats indicated that hyperalgesia, allodynia and, possibly, spontaneous pain were produced.
Abstract: A peripheral mononeuropathy was produced in adult rats by placing loosely constrictive ligatures around the common sciatic nerve. The postoperative behavior of these rats indicated that hyperalgesia, allodynia and, possibly, spontaneous pain (or dysesthesia) were produced. Hyperalgesic responses to noxious radiant heat were evident on the second postoperative day and lasted for over 2 months. Hyperalgesic responses to chemogenic pain were also present. The presence of allodynia was inferred from the nocifensive responses evoked by standing on an innocuous, chilled metal floor or by innocuous mechanical stimulation, and by the rats' persistence in holding the hind paw in a guarded position. The presence of spontaneous pain was suggested by a suppression of appetite and by the frequent occurrence of apparently spontaneous nocifensive responses. The affected hind paw was abnormally warm or cool in about one-third of the rats. About one-half of the rats developed grossly overgrown claws on the affected side. Experiments with this animal model may advance our understanding of the neural mechanisms of neuropathic pain disorders in humans.
5,121 citations
"Upregulation of the T-type calcium ..." refers background in this paper
...…that are similar to those in humans, such as mechanical and thermal hyperalgesia, as well as mechanical allodynia, have been reported to occur in experimental rat models of mechanical injury of peripheral nerves as a consequence of loose ligation of the sciatic nerve, a CCI (Bennett and Xie 1988)....
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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
"Upregulation of the T-type calcium ..." refers background in this paper
...I N T R O D U C T I O N For more than two decades, it has been recognized that T-type (low-voltage-activated) Ca2 channels (T-channels) have a key function in neuronal subthreshold membrane oscillations and spike firing in both the peripheral and CNS (reviewed in Perez-Reyes 2003)....
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TL;DR: The analysis of vanilloid receptor gene knockout mice confirms the involvement of this channel in pain sensation, as well as in hypersensitivity to noxious stimuli following tissue injury, and demonstrates the existence of redundant mechanisms for the sensation of heat-evoked pain.
Abstract: ▪ Abstract The detection of painful stimuli occurs primarily at the peripheral terminals of specialized sensory neurons called nociceptors. These small-diameter neurons transduce signals of a chemical, mechanical, or thermal nature into action potentials and transmit this information to the central nervous system, ultimately eliciting a perception of pain or discomfort. Little is known about the proteins that detect noxious stimuli, especially those of a physical nature. Here we review recent advances in the molecular characterization of the capsaicin (vanilloid) receptor, an excitatory ion channel expressed by nociceptors, which contributes to the detection and integration of pain-producing chemical and thermal stimuli. The analysis of vanilloid receptor gene knockout mice confirms the involvement of this channel in pain sensation, as well as in hypersensitivity to noxious stimuli following tissue injury. At the same time, these studies demonstrate the existence of redundant mechanisms for the sensation ...
1,507 citations
"Upregulation of the T-type calcium ..." refers background in this paper
...31510022-3077/08 $8.00 Copyright © 2008 The American Physiological Societywww.jn.org by 10.220.33.4 on O ctober 27, 2016 http://jn.physiology.org/ D ow nloaded from have confirmed that the vast majority of them are nociceptors (Caterina and Julius 2001; McCleskey and Gold 1999)....
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TL;DR: This review focuses on how both human studies and animal models are helping to elucidate the mechanisms underlying neuropathic pain, one of the surprisingly common disorders.
1,158 citations
TL;DR: The majority of research into neuropathic pain mechanisms has concentrated on changes in the peripheral nerve or spinal cord after peripheral nerve injury and most available evidence relates to changes in these parts of the nervous system and the review will, therefore, focus on these aspects.
Abstract: Neuropathic pain is defined as ‘pain initiated or caused by a primary lesion or dysfunction in the nervous system’. 94 The spectrum of neuropathic pain covers a variety of disease states (Table 1) and presents in the clinic with a variety of symptoms. 145 Neuropathic pain is often reported as having a lancinating or continuous burning character and is often associated with the appearance of abnormal sensory signs, such as allodynia (pain as a result of a stimulus which does not normally provoke pain) or hyperalgesia (an increased response to a stimulus which is normally painful) (Figure 1). The sensory phenomena can be further characterized into static or dynamic sub-types. The mechanistic implication of allodynia is that elements of the sensory nervous system, which normally signal innocuous sensation have begun to encode painful stimuli, whilst in hyperalgesia the structures that sub-serve nociception have become hyperexcitable. Neuropathic pain is an area of largely unmet therapeutic need. The current pharmacological mainstays of clinical management are tricyclic anti-depressants and certain anticonvulsants, 92 119 but these only achieve clinically significant (greater than 50%) pain relief in less than 50% of patients and are associated with sub-optimal side effect profiles. Opioids are generally considered to be less effective in neuropathic pain than in inflammatory pain, with the dose response curve of opioids in neuropathic pain shifted to the right of that for inflammatory pain, although the extent of this difference is controversial. 112 The majority of research into neuropathic pain mechanisms has concentrated on changes in the peripheral nerve or spinal cord after peripheral nerve injury and, therefore, most available evidence relates to changes in these parts of the nervous system and the review will, therefore, focus on these aspects. Nevertheless, it is important to recognize that alterations in the brain have also been demonstrated following peripheral nerve injury, but much less is known about the significance of these changes. For example, phantom limb pain has been shown to be associated with reorganization of the cortex of humans. 43 The degree of cortical re-organization, as determined by BTi neuromagnetic imaging, was linked in a linear fashion to the intensity of pain, with an increase in re-organization being associated with greater pain intensity. 43 A more recent study indicated that cortical re-organization was evident only in patients with phantom limb pain, and not in patients with non-painful phantom limb phenomena or congenital absence of the limb. 44
818 citations
"Upregulation of the T-type calcium ..." refers background in this paper
...…remodeling of other voltage- and ligand-gated ion channels that can alter the excitability of the sensory neurons has been proposed to have a critical function in the development and maintenance of neuropathic pain symptoms such as hyperalgesia and allodynia (Campbell and Meyer 2006; Woolf 2004)....
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