Are α9α10 Nicotinic Acetylcholine Receptors a Pain Target for α-Conotoxins?

Nevin, Simon T.; Clark, Richard J.; Klimis, Harry; Christie, MacDonald J.; Craik, David J.; Adams, David J.

doi:10.1124/mol.107.040568

Cited by 98 publications

(108 citation statements)

References 18 publications

(31 reference statements)

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“…We have previously shown that Vc1.1 is anti-allodynic in neuropathic pain models when administered intramuscularly, and that sustained reversal of allodynia appears due to GABA B -receptor-dependent inhibition of Ntype Ca 2+ channels because it is reversed by a selective GABA B -receptor antagonist (Klimis et al 2011). Furthermore, we observed no reversal of allodynia with peripheral administration of two analogs of Vc1.1, vc1a and [P60]Vc1.1 that exhibited no activity at GABA B receptor/N-type Ca 2+ channels but full activity at α9α10 nAChRs, suggesting that antagonism of α9α10 is not a requisite for anti-allodynia (Nevin et al 2007;Callaghan et al 2008). However, Vc1.1, AuIB and MII have markedly different (> 1000-fold) potencies for GABA B receptors/N-type calcium channels, with MII being nearly inactive.…”

Section: Discussionmentioning

confidence: 62%

“…Vc1.1 and RgIA are both potent antagonists of α9α10 nAChRs, suggesting this may be the anti-allodynia target (Vincler et al 2006). However, MII and AuIB are both devoid of activity at α9α10 nAChRs (McIntosh et al 1999;Callaghan et al 2008;Azam and McIntosh 2009;Callaghan and Adams 2010;Klimis et al 2011) and other -conotoxin analogues that act on these nAChRs fail to inhibit allodynia (Nevin et al 2007). Moreover, 910 nAChRs show very limited tissue distribution, being expressed predominantly in the olivochochlear system (Vetter et al, 2007) and their role in sensory nerve function is unclear.…”

Section: Introductionmentioning

confidence: 99%

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Intrathecal α-conotoxins Vc1.1, AuIB and MII acting on distinct nicotinic receptor subtypes reverse signs of neuropathic pain

et al. 2012

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The large diversity of peptides from venomous creatures with high affinity for molecules involved in the development and maintenance of neuropathic pain has led to a surge in venom-derived analgesic research. Some members of the α-conotoxin family from Conus snails which specifically target subtypes of nicotinic acetylcholine receptors (nAChR) have been shown to be effective at reducing mechanical allodynia in neuropathic pain models. We sought to determine if three such peptides, Vc1.1, AuIB and MII were effective following intrathecal administration in a rat neuropathic pain model because they exhibit different affinities for the major putative pain relieving targets of α-conotoxins. Intrathecal administration of α-conotoxins, Vc1.1, AuIB and MII into neuropathic rats reduced mechanical allodynia for up to 6 hours without significant side effects. In vitro patch-clamp electrophysiology of primary afferent synaptic transmission revealed the mode of action of these toxins was not via a GABA B -dependant mechanism, and is more likely related to their action at nAChRs containing combinations of α3, α7 or other subunits. Intrathecal nAChR subunitselective conotoxins are therefore promising tools for the effective treatment of neuropathic pain. AbstractThe large diversity of peptides from venomous creatures with high affinity for molecules involved in the development and maintenance of neuropathic pain has led to a surge in venom-derived analgesic research. Some members of the α-conotoxin family from Conus snails which specifically target subtypes of nicotinic acetylcholine receptors (nAChR) have been shown to be effective at reducing mechanical allodynia in neuropathic pain models. We sought to determine if three such peptides, Vc1.1, AuIB and MII were effective following intrathecal administration in a rat neuropathic pain model because they exhibit different affinities for the major putative pain relieving targets of α-conotoxins. Intrathecal administration of α-conotoxins, Vc1.1, AuIB and MII into neuropathic rats reduced mechanical allodynia for up to 6 hours without significant side effects. In vitro patch-clamp electrophysiology of primary afferent synaptic transmission revealed the mode of action of these toxins was not via a GABA B -dependant mechanism, and is more likely related to their action at nAChRs containing combinations of α3, α7 or other subunits. Intrathecal nAChR subunitselective conotoxins are therefore promising tools for the effective treatment of neuropathic pain.3

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Section: Discussionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Intrathecal α-conotoxins Vc1.1, AuIB and MII acting on distinct nicotinic receptor subtypes reverse signs of neuropathic pain

et al. 2012

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“…Recovery of nerve function retained Nevin et al, 2007 Rg1A Partially reverses mechanical allodynia in several neuropathic models after intramuscular dosing. human sural nerve to nicotine (Lang et al, 2005).…”

Section: Very Weak ␣9␣10mentioning

confidence: 99%

“…A more plausible hypothesis was forwarded by Vincler and McIntosh (2007), who suggested the analgesic efficacy of ␣-conotoxins that inhibit ␣9␣10 nAChRs was due to inhibition of immune cell migration to injured nerves, although it remains to be determined whether this process is modulated by ␣9␣10 nAChRs. However, two analogs of Vc1.1, Vc1a and [P6O]Vc1.1, retain full activity ␣9␣10 nAChRs but lose activity at other targets (see below) and fail to reverse allodynia in a neuropathic pain model (Nevin et al, 2007). Conversely, ␣-AuIB and ␣-MII are efficacious in a neuropathic pain model but do not inhibit ␣9␣10 nAChRs (Klimis et al, 2011).…”

Section: Very Weak ␣9␣10mentioning

confidence: 99%

Conus Venom Peptide Pharmacology

Lewis¹,

Dutertre²,

Vetter³

et al. 2012

Pharmacol Rev

387

424

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“…Nicotine was used for the ␣7 nAChRs to avoid the partial agonist effect of choline because of the potential breakdown of ACh. Toxins and agonists were applied as described (15) or by the OpusXpress drug delivery system (18). Peak current amplitudes were measured before and following 180 or 200 s incubation of the GID analogues.…”

Section: Functional Characterizationmentioning

confidence: 99%

Inhibition of Neuronal Nicotinic Acetylcholine Receptor Subtypes by α-Conotoxin GID and Analogues

Millard

Nevin

Loughnan

et al. 2009

Journal of Biological Chemistry

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␣-Conotoxins are small disulfide-rich peptides from the venom of the Conus species that target the nicotinic acetylcholine receptor (nAChR). They are valuable pharmacological tools and also have potential therapeutic applications particularly for the treatment of chronic pain. ␣-Conotoxin GID is isolated from the venom of Conus geographus and has an unusual N-terminal tail sequence that has been shown to be important for binding to the ␣4␤2 subtype of the nAChR. To date, only four conotoxins that inhibit the ␣4␤2 subtype have been characterized, but they are of considerable interest as it is the most abundant nAChR subtype in the mammalian brain and has been implicated in a range of diseases. In this study, analysis of alanine-scan and truncation mutants of GID reveals that a conserved proline in ␣-conotoxins is important for activity at the ␣7, ␣3␤2, and ␣4␤2 subtypes. Although the proline residue was the most critical residue for activity at the ␣3␤2 subtype, Asp 3 , Arg 12 , and Asn 14 are also critical at the ␣7 subtype. Interestingly, very few of the mutations tested retained activity at the ␣4␤2 subtype indicating a tightly defined binding site. This lack of tolerance to sequence variation may explain the lack of selective ligands discovered for the ␣4␤2 subtype to date. Overall, our findings contribute to the understanding of the structureactivity relationships of ␣-conotoxins and may be beneficial for the ongoing attempts to exploit modulators of the neuronal nAChRs as therapeutic agents.␣-Conotoxins are small, disulfide-rich peptide toxins isolated from the venom of predatory marine snails of the Conus genus and are generally 12-19 amino acids in length (1, 2). These toxins competitively and specifically inhibit muscle and neuronal nicotinic acetylcholine receptor (nAChR) 3 subtypes (3) and are valuable tools in understanding the mechanisms involved in ligand-receptor interactions (4). There is much current interest in the study of various neuronal nAChR receptor subtypes implicated in diverse neurological disorders such as Alzheimer disease, epilepsy, and pain (5, 6) and in the regulation of small-cell lung carcinoma (7, 8). ␣-Conotoxin GID is a 19-residue peptide isolated from the venom of Conus geographus that has the amino acid sequence IRD␥CCSNPACRVNNOHVC (9). Notable features of its sequence include a four-residue extended N-terminal "tail" upstream of the first cysteine, two post-translationally modified residues, ␥-carboxyglutamic acid (Gla) and hydroxyproline (Hyp), and the fact that it lacks an amidated C terminus typical of most ␣-conotoxins. The three-dimensional structure of GID includes the classic two-loop structural motif of the ␣-conotoxins, but the N-terminal tail is disordered in solution, as shown in Fig. 1. GID selectively inhibits the ␣7, ␣3␤2, and ␣4␤2 subtypes of the neuronal nAChR, with high potency, with IC 50 values of 4.5, 3.1, and 152 nM, respectively (9). Deletion of the N-terminal four residues [⌬1-4]GID has been shown to significantly decrease activity at the ␣4␤2 recepto...

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Are α9α10 Nicotinic Acetylcholine Receptors a Pain Target for α-Conotoxins?

Abstract: The synthetic ␣-conotoxin Vc1

Cited by 98 publications

References 18 publications

Intrathecal α-conotoxins Vc1.1, AuIB and MII acting on distinct nicotinic receptor subtypes reverse signs of neuropathic pain

Intrathecal α-conotoxins Vc1.1, AuIB and MII acting on distinct nicotinic receptor subtypes reverse signs of neuropathic pain

Conus Venom Peptide Pharmacology

Inhibition of Neuronal Nicotinic Acetylcholine Receptor Subtypes by α-Conotoxin GID and Analogues

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