Targeting Ca2+ channels to treat pain: T-type versus N-type

doi:10.1016/j.tips.2004.07.004

Trends in Pharmacological Sciences

Volume 25, Issue 9, September 2004, Pages 465-470

https://doi.org/10.1016/j.tips.2004.07.004 Get rights and content

The transmission of pain signals at the spinal level is crucially dependent on voltage-gated Ca²⁺ channels in nociceptive neurons. Pharmacological and gene-knockout studies implicate N-type Ca²⁺ channels as key mediators of nociceptive signaling in dorsal root ganglion (DRG) neurons, and as potential targets for the development of analgesic drugs. Furthermore, nociceptor-specific alternative splicing of the gene encoding N-type Ca²⁺ channels might provide strategies for splice-isoform-specific drug targeting. More recently, T-type Ca²⁺ channels have been implicated in the processing of pain signals at both spinal and thalamic levels. However, although inhibition of T-type channel activity in DRG neurons mediates analgesia, gene knockout of T-type channels in the CNS is reported to increase the perception of visceral pain. In this review, we discuss the implications of these findings for the design of novel therapeutic strategies and contrast the role of T-type channels with that of N-type channels in pain transmission and analgesia.

Section snippets

N-type Ca²⁺ channels and pain

Several lines of evidence implicate N-type Ca²⁺ (Ca_v2.2) channels in the transmission of pain signals at the spinal level. These channels are expressed exclusively in neuronal tissue and their expression is particularly high in the superficial layer of the dorsal horn, which is considered to be the nociceptive area of the spinal cord. Blockers of N-type channels stop the release of neuropeptides such as substance P [9]. N-type channels are also inhibited potently by mu opioid peptide receptor

T-type channels: novel targets for treating pain

A hallmark of neuropathic and inflammatory pain is hyperexcitability of nociceptive neurons. This can result in conditions of spontaneous pain (pain sensation without any peripheral stimulation), allodynia (where a stimulus that is normally non-noxious becomes noxious) and hyperalgesia (decreased nociceptive threshold). Enhanced nociceptor excitability has been linked to increased activity of tetrodotoxin (TTX)-resistant Na⁺ channels in models of inflammatory pain [23]; however, it is

α₂–δ-subunits and pain

Systemic administration of the anticonvulsant gabapentin, a GABA analog, produces effective analgesia in patients with neuropathic pain, particularly in syndromes such as diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia and migraine [39]. It is suggested that gabapentin acts postsynaptically to modulate transmission at glutamatergic synapses [40]. It is also reported that gabapentin might act via activation of GABA_B receptors [41], but this is controversial [42]. Gabapentin

Concluding remarks

The treatment of chronic and neuropathic pain remains an area of utmost priority. Whereas N-type Ca²⁺ channels have long been recognized as suitable targets for pain management, strategies for direct inhibition of N-type Ca²⁺ channels by peptide toxins and small, organic blockers have been realized only recently. Moreover, we are beginning to learn of potential ways to target N-type Ca²⁺ channels specifically in nociceptors. T-type Ca²⁺ channels are also potential targets in the treatment of

Acknowledgements

G.W.Z. holds faculty awards from the Alberta Heritage Foundation for Medical Research (AHFMR) and the Canada Research Chairs program. C.A. is funded by postdoctoral awards from the AHFMR and the Heart and Stroke Foundation of Canada. We thank Natalie Vergnolle for helpful comments on the manuscript.

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In this context, it would be interesting to investigate whether the differential regulation of the nociceptive pathways by alternative splicing of N-type channels is related to their interaction with Cdk5. Likewise, considering that the N-type channels play essential roles in nociception, their inhibition is a promising strategy for treating chronic pain (Altier and Zamponi, 2004; Bourinet et al., 2014; Chew and Khanna, 2018; Jurkovicova-Tarabova and Lacinova, 2019). This could be achieved by directly blocking the channel, inhibiting its trafficking to the cell membrane, or modifying the signaling pathways that regulate it, including that of Cdk5 (Altier and Zamponi, 2004; Altier et al., 2007; Su et al., 2012; Alles and Smith, 2018).
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Cav2.2 deficient mice exhibit hyposensitivity to inflammatory and neuropathic pain [16–18]. Hence, this channel is considered as an important target for treating nociceptive and neuropathic pain [19–22]. Cav2.2 is a transmembrane VGCC that is involved in various cell signaling responses and membrane potential alterations that induce calcium influx.
Chronic neuropathic pain is the most complex and challenging clinical problem of a population that sets a major physical and economic burden at the global level. Ca²⁺-permeable channels functionally orchestrate the processing of pain signals. Among them, N-type voltage-gated calcium channels (VGCC) hold prominent contribution in the pain signal transduction and serve as prime targets for synaptic transmission block and attenuation of neuropathic pain. Here, we present detailed in silico analysis to comprehend the underlying conformational changes upon Ca²⁺ ion passage through Ca_v2.2 to differentially correlate subtle transitions induced via binding of a conopeptide-mimetic alkylphenyl ether-based analogue MVIIA. Interestingly, pronounced conformational changes were witnessed at the proximal carboxyl-terminus of Ca_v2.2 that attained an upright orientation upon Ca⁺² ion permeability. Moreover, remarkable changes were observed in the architecture of channel tunnel. These findings illustrate that inhibitor binding to Ca_v2.2 may induce more narrowing in the pore size as compared to Ca²⁺ binding through modulating the hydrophilicity pattern at the selectivity region. A significant reduction in the tunnel volume at the selectivity filter and its enhancement at the activation gate of Ca⁺²-bound Ca_v2.2 suggests that ion binding modulates the outward splaying of pore-lining S6 helices to open the voltage gate. Overall, current study delineates dynamic conformational ensembles in terms of Ca⁺² ion and MVIIA-associated structural implications in the Ca_v2.2 that may help in better therapeutic intervention to chronic and neuropathic pain management.
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Small-diameter DRG neurons were classified into IB₄+ (nonpeptidergic) and IB₄- (peptidergic). Intracellular [Ca²⁺] microfluorometry and voltage-clamp experiments showed that quinpirole reduced Ca²⁺ influx and inhibited the high voltage-activated Ca²⁺ current (HVA-I_Ca) in half of IB₄+ neurons, leaving Ca²⁺ entry and HVA-I_Ca in IB₄- neurons nearly unaffected. Pretreatment with ω-conotoxin MVIIA prevented the effect of quinpirole on HVA-I_Ca from IB₄+ neurons, indicating that quinpirole mainly inhibits Ca_V2.2 channels. Immunofluorescence experiments showed that D2 DA receptor was present mainly in IB₄+ small DRG neurons. Finally, in behavioral experiments in rats, the clinically approved D2-like receptor agonist pramipexole produced spinal antinociception in a similar fashion to quinpirole, with a significant effect only in the mechanonociceptive test. Our results explain, at least in part, why D2-like receptor agonists produce antinociception on mechanonociceptors.
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Sensory cross-activation is still ill-defined and research concerning the consequences of sensory mergence on normal brain function is very limited. Human studies describe behavioral benefits of people with synesthesia- a peculiar form of perception possibly due to cross-modal activation- regarding sensory and memory abilities. Here, we studied behavioral alterations in calcium channel (CACN) subunit α2δ3 knockout (KO) mice exhibiting pain-induced cortical cross-modal activation. Knockout mice exhibited an increased response upon touch of a pinna and impaired audition, while elementary olfaction, vision, somatosensation and motor function were not altered. In contrast to synesthetic humans for whom enhanced memory function had been described, α2δ3 KO mice might have developed defects for object-based memory. However, in a task requiring use of multiple modalities, mutant mice revealed an enhanced performance compared to wild-type controls. Furthermore, several tests revealed evidence for increased anxiety-like behavior of α2δ3 KO animals. In summary, deficits in single sensory abilities and a potential gain in processing simultaneous sensory information in α2δ3 KO mice might represent behavioral correlates of sensory cross-activation. Further, our data suggest a role of CACNα2δ3 within the functionality of the sensory system, but not the motor system and general health.
The Disease-modifying Drug Candidate, SAK3 Improves Cognitive Impairment and Inhibits Amyloid beta Deposition in App Knock-in Mice
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Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common form of elderly dementia in the world. At present, acetylcholine inhibitors, such as donepezil, galantamine and rivastigmine, are used for AD therapy, but the therapeutic efficacy is limited. We recently proposed T-type voltage-gated Ca²⁺ channels’ (T-VGCCs) enhancer as a new therapeutic candidate for AD. In the current study, we confirmed the pharmacokinetics of SAK3 in the plasma and brain of mice using ultra performance liquid chromatography-tandem mass spectrometry. We also investigated the effects of SAK3 on the major symptoms of AD, such as cognitive dysfunction and amyloid beta (Aβ) accumulation, in App^NL-F knock-in (NL-F) mice, which have been established as an AD model. Chronic SAK3 (0.5 mg/kg/day) oral administration for 3 months from 9 months of age improved cognitive function and inhibited Aβ deposition in 12-month-old NL-F mice. Using microarray and real-time PCR analysis, we discovered serum- and glucocorticoid-induced protein kinase 1 (SGK1) as one of possible genes involved in the inhibition of Aβ deposition and improvement of cognitive function by SAK3. These results support the idea that T-VGCC enhancer, SAK3 could be a novel candidate for disease-modifying therapeutics for AD.
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Enhanced sensation of pain in inflamed tissues, be it triggered by mechanical, thermal, or chemical forces, is referred to as allodynia and hyperalgesia. Whereas the former can be provoked by otherwise nonpainful stimulation, the latter is an exaggerated reaction to stimuli that can be considered painful. The relevant pathological mechanism is the release of several mediators from various types of cells that contribute to inflammation. These inflammatory agents are collectively referred to as the “inflammatory soup,” and serotonin is one prominent representative thereof. The general mechanism that leads to enhanced pain sensation is the sensitization of nociceptors by serotonin and other inflammatory mediators. This chapter describes basic principles of nociception and pain sensation (defined below) and reveals how serotonin can impinge on the underlying physiological processes. Most of the known serotonin receptor subtypes have been reported to be able to mediate sensitization of nociceptors. The associated signaling cascades target a variety of different ion channels that are either involved in the transduction of noxious stimuli into neuronal action potentials or in the propagation of the nociceptive information to the appropriate brain areas.

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Trends in Pharmacological Sciences

Targeting Ca2+ channels to treat pain: T-type versus N-type

Section snippets

N-type Ca2+ channels and pain

T-type channels: novel targets for treating pain

α2–δ-subunits and pain

Concluding remarks

Acknowledgements

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