α9-Nicotinic Acetylcholine Receptors Contribute to the Maintenance of Chronic Mechanical Hyperalgesia, but Not Thermal or Mechanical Allodynia

Mohammadi, Sarasa A.; Christie, MacDonald J.

doi:10.1186/1744-8069-10-64

Cited by 38 publications

(39 citation statements)

References 51 publications

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“…Several studies have shown that some α-conotoxins block VGCCs via stimulation of GABA B receptors, suggesting that antinociceptive effects were mediated through blockade of N-type calcium channels (28)(29)(30)(31)(32)(33). However, some studies have not fully reproduced this effect (34,35), and we show that GeXIVA fails to block VGCCs. Because GeXIVA is active at α9α10 nAChRs, but not VGCCs, our findings provide support for the involvement of α9α10 nAChRs in pain sensation.…”

Section: Discussionmentioning

confidence: 44%

Cloning, synthesis, and characterization of αO-conotoxin GeXIVA, a potent α9α10 nicotinic acetylcholine receptor antagonist

Luo

Zhangsun

Harvey

et al. 2015

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

197

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We identified a previously unidentified conotoxin gene from Conus generalis whose precursor signal sequence has high similarity to the O1-gene conotoxin superfamily. The predicted mature peptide, αO-conotoxin GeXIVA (GeXIVA), has four Cys residues, and its three disulfide isomers were synthesized. Previously pharmacologically characterized O1-superfamily peptides, exemplified by the US Food and Drug Administration-approved pain medication, ziconotide, contain six Cys residues and are calcium, sodium, or potassium channel antagonists. However, GeXIVA did not inhibit calcium channels but antagonized nicotinic AChRs (nAChRs), most potently on the α9α10 nAChR subtype (IC50 = 4.6 nM). Toxin blockade was voltage-dependent, and kinetic analysis of toxin dissociation indicated that the binding site of GeXIVA does not overlap with the binding site of the competitive antagonist α-conotoxin RgIA. Surprisingly, the most active disulfide isomer of GeXIVA is the bead isomer, comprising, according to NMR analysis, two well-resolved but uncoupled disulfide-restrained loops. The ribbon isomer is almost as potent but has a more rigid structure built around a short 310-helix. In contrast to most α-conotoxins, the globular isomer is the least potent and has a flexible, multiconformational nature. GeXIVA reduced mechanical hyperalgesia in the rat chronic constriction injury model of neuropathic pain but had no effect on motor performance, warranting its further investigation as a possible therapeutic agent.

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Section: Discussionmentioning

confidence: 44%

Cloning, synthesis, and characterization of αO-conotoxin GeXIVA, a potent α9α10 nicotinic acetylcholine receptor antagonist

Luo

Zhangsun

Harvey

et al. 2015

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

197

View full text Add to dashboard Cite

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“…Subsequent reports indicated that Vc1.1 has potent GABA B agonist activity (Berecki et al, 2014; Callaghan and Adams, 2010; Callaghan et al, 2008; Castro et al, 2016; Cuny et al, 2012; Huynh et al, 2015; Klimis et al, 2011; Nevin et al, 2007; van Lierop et al, 2013). These findings have prompted an ongoing debate as to whether the analgesic mechanism of action of the α-conotoxins is via α9α10 nAChRs and/ or GABA B receptors (Adams and Berecki, 2013; Mohammadi and Christie, 2014; Mohammadi and Christie, 2015; Wright et al, 2015). The pharmacological profile of GeXIVA coupled with its demonstrated analgesia in rat models of neuropathic pain has prompted further interest in α9α10 nAChRs and GeXIVA as a potential therapeutic agent (Luo et al, 2015, Li et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

αO-Conotoxin GeXIVA disulfide bond isomers exhibit differential sensitivity for various nicotinic acetylcholine receptors but retain potency and selectivity for the human α9α10 subtype

et al. 2017

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Nicotinic acetylcholine receptor (nAChR) subtypes exhibit distinct neuropharmacological properties that are involved in a range of neuropathological conditions, including pain, addiction, epilepsy, autism, schizophrenia, Tourette’s syndrome, Alzheimer’s and Parkinson’s diseases, as well as many types of cancer. The α9α10 nAChR is a potential target in chronic pain, wound healing, the pathophysiology of the auditory system, and breast and lung cancers. αO-conotoxin GeXIVA is a potent antagonist of rat α9α10 nAChRs, with the ‘bead’ disulfide bond isomer displaying the lowest IC50 of the three possible isomers. In the rat chronic constriction injury model of neuropathic pain, this isomer reduced mechanical hyperalgesia without affecting motor performance. Here, we report the effects of the three disulfide bond isomers of GeXIVA on human α9α10 nAChRs, other human nAChR subtypes, various rat nAChR subtypes, and 10 rat α9α10 nAChR mutants. The three isomers displayed only ~5-fold difference in potency on the human vs rat α9α10 receptors and had similar affinities at wild-type rat α9α10 nAChRs and all 10 α9α10 receptor mutants. From these findings, the binding site and mechanism of action of GeXIVA on rat and human α9α10 nAChR was deduced to be different from that of other conotoxins targeting this nAChR subtype. GeXIVA is therefore a unique ligand that might prove useful for further probing of binding sites on the α9α10 nAChR.

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“…Notably, N-type calcium channels may be inhibited by stimulation of γ-aminobutyric acid type-B (GABA B ) receptors or µ-opioid receptors [44][45][46]. The stimulation of GABA B receptors has been proposed as the mechanism of action for α-conotoxins Vc1.1 and RgIA [47][48][49][50][51][52]. We note, however, that the RgIA analog used in the present study, RgIA4, does not have GABA B or µ-opioid activity [24,25].…”

Section: α9α10 Nachrs As a Target For Pain Treatmentmentioning

confidence: 99%

RgIA4 Accelerates Recovery from Paclitaxel-Induced Neuropathic Pain in Rats

et al. 2019

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Chemotherapeutic drugs are widely utilized in the treatment of human cancers. Painful chemotherapy-induced neuropathy is a common, debilitating, and dose-limiting side effect for which there is currently no effective treatment. Previous studies have demonstrated the potential utility of peptides from the marine snail from the genus Conus for the treatment of neuropathic pain. α-Conotoxin RgIA and a potent analog, RgIA4, have previously been shown to prevent the development of neuropathy resulting from the administration of oxaliplatin, a platinum-based antineoplastic drug. Here, we have examined its efficacy against paclitaxel, a chemotherapeutic drug that works by a mechanism of action distinct from that of oxaliplatin. Paclitaxel was administered at 2 mg/kg (intraperitoneally (IP)) every other day for a total of 8 mg/kg. Sprague Dawley rats that were co-administered RgIA4 at 80 µg/kg (subcutaneously (SC)) once daily, five times per week, for three weeks showed significant recovery from mechanical allodynia by day 31. Notably, the therapeutic effects reached significance 12 days after the last administration of RgIA4, which is suggestive of a rescue mechanism. These findings support the effects of RgIA4 in multiple chemotherapeutic models and the investigation of α9α10 nicotinic acetylcholine receptors (nAChRs) as a non-opioid target in the treatment of chronic pain.Patients have exhibited several types of neuropathies, including numbness, chronic pain, and allodynia (painful hypersensitivity) to mechanical or thermal stimuli [5]. Amongst patients, however, the type, duration, and severity of neuropathy can vary [6]. While the prevalence and manifestations of paclitaxel-induced neuropathy have been well documented, the underlying mechanisms are still being characterized. Several adjuvant treatments have been used in an attempt to combat the effects of chemotherapy-induced peripheral neuropathy (CIPN). However, there are currently no FDA-approved medications for the prevention or treatment of CIPN.Cone snails have historically displayed a repertoire of therapeutic molecules. The venomous marine gastropods of the genus Conus are a diverse collection of snails that have developed complex hunting and envenomation strategies. The venoms of these snails contain hundreds of unique peptides, and the contents of these venoms can also change in response to defensive or predatory stimuli [7]. Cone snails have refined a suite of bioactive peptides that can exquisitely and potently discriminate among receptors involved in neurotransmission. These targets include G-protein-coupled receptors and voltage-and ligand-gated ion channels [8]. The chemical arsenal of each snail also contains bioactive compounds that have been characterized as prey-endogenous mimetics, such as the insulin-like peptide used by Conus geographus, which more closely resembles fish insulin than its own [9]. The discovery of this molecular mimicry strategy spurred the characterization of several other hormone/neuropeptide-like peptides in the venom reperto...

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α9-Nicotinic Acetylcholine Receptors Contribute to the Maintenance of Chronic Mechanical Hyperalgesia, but Not Thermal or Mechanical Allodynia

Cited by 38 publications

References 51 publications

Cloning, synthesis, and characterization of αO-conotoxin GeXIVA, a potent α9α10 nicotinic acetylcholine receptor antagonist

Cloning, synthesis, and characterization of αO-conotoxin GeXIVA, a potent α9α10 nicotinic acetylcholine receptor antagonist

αO-Conotoxin GeXIVA disulfide bond isomers exhibit differential sensitivity for various nicotinic acetylcholine receptors but retain potency and selectivity for the human α9α10 subtype

RgIA4 Accelerates Recovery from Paclitaxel-Induced Neuropathic Pain in Rats

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