Voltage‐Gated Calcium Channels as Targets for the Treatment of Chronic Pain

McGivern, Joseph G.

doi:10.1002/9780470522226.ch5

Cited by 20 publications

(24 citation statements)

References 143 publications

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“…The finding that ML382 can inhibit pain after injury without exogenous BAM peptide further supports this notion. N-type HVA calcium channels play an important role in controlling the release of neurotransmitter vesicles from central terminals of nociceptive DRG neurons into spinal cord (33,34,36,37,55). Accordingly, N-type channels have been important targets for the development of drugs to treat pain (33,34,56).…”

Section: Discussionmentioning

confidence: 99%

“…We then examined if MRGPRX1 is functional at the cellular level. Activation of Ca V 2.2 N-type HVA calcium channels at central terminals of primary sensory neurons is critical to excitatory neurotransmitter release into the spinal cord, which transduces sensory information toward the CNS (33,34). DRG neurons express at least three types of HVA Ca 2+ channels, namely, Ca V 2.2 N-type, Ca V 2.1 P/Q-type, and Ca V 1.1/ Ca V 1.4 L-type (35,36).…”

Section: Bam8-22mentioning

confidence: 99%

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Targeting human Mas-related G protein-coupled receptor X1 to inhibit persistent pain

Tseng

Tiwari

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Human Mas-related G protein-coupled receptor X1 (MRGPRX1) is a promising target for pain inhibition, mainly because of its restricted expression in nociceptors within the peripheral nervous system. However, constrained by species differences across Mrgprs, drug candidates that activate MRGPRX1 do not activate rodent receptors, leaving no responsive animal model to test the effect on pain in vivo. Here, we generated a transgenic mouse line in which we replaced mouse Mrgprs with human MrgprX1. This humanized mouse allowed us to characterize an agonist [bovine adrenal medulla 8-22 (BAM8-22)] and a positive allosteric modulator (PAM), ML382, of MRGPRX1. Cellular studies suggested that ML382 enhances the ability of BAM8-22 to inhibit high-voltage-activated Ca 2+ channels and attenuate spinal nociceptive transmission. Importantly, both BAM8-22 and ML382 effectively attenuated evoked, persistent, and spontaneous pain without causing obvious side effects. Notably, ML382 by itself attenuated both evoked pain hypersensitivity and spontaneous pain in MrgprX1 mice after nerve injury without acquiring coadministration of an exogenous agonist. Our findings suggest that humanized MrgprX1 mice provide a promising preclinical model and that activating MRGPRX1 is an effective way to treat persistent pain.pain | DRG neurons | MrgprX1 | GPCR | positive allosteric modulator P ersistent pain is a major healthcare problem that remains difficult to manage. Commonly used analgesics (e.g., opioids) often lead to an array of adverse side effects (e.g., sedation, addiction, toxicity) that further deteriorate life quality (1, 2). An important reason why most pain medicines produce dose-limiting side effects is the broad expression of drug targets (e.g., opioid receptors, cyclooxygenase-2) in the central nervous system (CNS) and outside of pain pathways (e.g., cardiovascular system) (3). Because persistent pain is often primed with peripheral pathological conditions, such as tissue inflammation and nerve injury, and its maintenance is also attributable to peripheral neuronal sensitization (4, 5), development of pain-specific treatments would greatly benefit from the identification of novel targets specifically expressed in pain pathways, especially those targets on nociceptive primary sensory neurons (6).One potential target is the Mas-related G protein-coupled receptor (MRGPR). MRGPRs comprise a family of orphan G protein-coupled receptors (GPCRs) and include many genes in humans and rodents (7-11), but their physiological functions are only partially known. Many Mrgpr genes (mouse MrgprA3, MrgprC11, and MrgprD; rat MrgprC; and human MrgprX1) are expressed specifically in small-diameter primary sensory dorsal root ganglia (DRG) neurons (presumably nociceptive) in rodents, monkeys, and humans discovered using various approaches, and have been reported to play important roles in pain and itch (6, 10, 12-19).Animal studies suggest that a potential drug target is the MRGPRC in trigeminal ganglia and DRG (6,20,21). Activation of MRGPRC with agon...

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Section: Discussionmentioning

confidence: 99%

Section: Bam8-22mentioning

confidence: 99%

Targeting human Mas-related G protein-coupled receptor X1 to inhibit persistent pain

Tseng

Tiwari

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Electrical abnormalities mediated through these VGCCs isoforms present concomitantly with induced pain states in animal models, supporting their critical role in the generation and maintenance of neuropathic pain [29]. Although some studies also suggest roles for P/Q- and R-type VGCCs in the neurotransmission of pathologic pain, these isoforms have not yet been validated as analgesic targets in humans [35,36,37,38,39]. …”

Section: Vgccs and Their Role In Neuropathic Painmentioning

confidence: 99%

Omega-Conotoxins as Experimental Tools and Therapeutics in Pain Management

Hannon

Atchison

2013

Marine Drugs

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Neuropathic pain afflicts a large percentage of the global population. This form of chronic, intractable pain arises when the peripheral or central nervous systems are damaged, either directly by lesion or indirectly through disease. The comorbidity of neuropathic pain with other diseases, including diabetes, cancer, and AIDS, contributes to a complex pathogenesis and symptom profile. Because most patients present with neuropathic pain refractory to current first-line therapeutics, pharmaceuticals with greater efficacy in pain management are highly desired. In this review we discuss the growing application of ω-conotoxins, small peptides isolated from Conus species, in the management of neuropathic pain. These toxins are synthesized by predatory cone snails as a component of paralytic venoms. The potency and selectivity with which ω-conotoxins inhibit their molecular targets, voltage-gated Ca2+ channels, is advantageous in the treatment of neuropathic pain states, in which Ca2+ channel activity is characteristically aberrant. Although ω-conotoxins demonstrate analgesic efficacy in animal models of neuropathic pain and in human clinical trials, there remains a critical need to improve the convenience of peptide drug delivery methods, and reduce the number and severity of adverse effects associated with ω-conotoxin-based therapies.

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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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Voltage‐Gated Calcium Channels as Targets for the Treatment of Chronic Pain

Cited by 20 publications

References 143 publications

Targeting human Mas-related G protein-coupled receptor X1 to inhibit persistent pain

Targeting human Mas-related G protein-coupled receptor X1 to inhibit persistent pain

Omega-Conotoxins as Experimental Tools and Therapeutics in Pain Management

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

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