Therapeutic applications of conotoxins that target the neuronal nicotinic acetylcholine receptor

Livett, Bruce G.; Sandall, David; Keays, David A.; Down, J. G.; Gayler, Kenwyn R.; Satkunanathan, Narmatha; Khalil, Zeinab

doi:10.1016/j.toxicon.2006.07.023

Cited by 123 publications

(104 citation statements)

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“…Several nicotinic agonists are analgesic and have entered phase I clinical trials, but these agonists have also suffered from a variety of side effects due to a lack of nAChR subtype specificity. Conversely, the nAChR antagonist Vc1.1 has produced analgesia in a variety of pain models in animals and has currently entered phase II clinical trials (18). The data presented here reveal a molecular target in the treatment of neuropathic pain, the ␣9␣10 nAChR subtype.…”

Section: Discussionmentioning

confidence: 85%

“…However, potent antagonists that block these subtypes are not analgesic. Furthermore, if block of ␣3(␣5)␤2 and ␣3(␣5)␤4 nAChRs were the analgesic mechanism of action, one might expect the drug to produce hypotension through antagonism of autonomic ganglionic receptors, a side effect not reported in animal or human clinical trials (18). Given these inconsistent observations, the mechanism of analgesia for Vc1.1 was reinvestigated; we show Vc1.1 to be similar to RgIA in a number of ways.…”

Section: Vc1mentioning

confidence: 78%

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Molecular mechanism for analgesia involving specific antagonism of α9α10 nicotinic acetylcholine receptors

Vincler

Wittenauer

Parker

et al. 2006

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

213

264

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␣9␣10 nicotinic acetylcholine receptors (nAChRs) have been identified in a variety of tissues including lymphocytes and dorsal root ganglia; except in the case of the auditory system, the function of ␣9␣10 nAChRs is not known. Here we show that selective block (rather than stimulation) of ␣9␣10 nAChRs is analgesic in an animal model of nerve injury pain. In addition, blockade of this nAChR subtype reduces the number of choline acetyltransferase-positive cells, macrophages, and lymphocytes at the site of injury. Chronic neuropathic pain is estimated to affect up to 8% of the world's population; the numerous analgesic compounds currently available are largely ineffective and act through a small number of pharmacological mechanisms. Our findings not only suggest a molecular mechanism for the treatment of neuropathic pain but also demonstrate the involvement of ␣9␣10 nAChRs in the pathophysiology of peripheral nerve injury.N europathic pain is a prolonged, debilitating state characterized by allodynia (pain produced by previously innocuous stimuli), hyperalgesia (an increased or exaggerated response to painful stimuli), and spontaneous pain. Neuropathic pain is often refractory to conventional pain therapeutics such as opioids and nonsteroidal antiinflammatory agents and, therefore, represents a large, unmet clinical need. Neuropathic pain can be triggered in a variety of ways; injury to a peripheral nerve is one of the most common causes.The involvement of nicotinic acetylcholine receptors (nAChRs) in pain has been suggested by a number of experimental observations, and the administration of nAChR agonists reduces pain-related behaviors in several animal models (1-5). nAChRs are pentameric ligand-gated ion channels composed of ␣ (␣1-␣10) and non-␣ (␤1-␤4, , ␥, and ␦) subunits. The ␣2-␣6 and ␤2-␤4 subunits form heteromeric channels consisting of a combination of ␣ and ␤ subunits (6). Homomeric channels can be formed by ␣7 or ␣9 subunits; the ␣10 subunit will only form functional receptors when it is expressed with the ␣9 subunit (6). Many of the nAChRs show widespread patterns of neuronal and nonneuronal distribution; ␣9 and/or ␣10 subunits have been reported within hair cells of the inner ear (7), sperm (8), dorsal root ganglion neurons (9), skin keratinocytes (10), the pars tuberalis of the pituitary (11), and lymphocytes (12). The function of ␣9␣10 nAChRs in the auditory system has been well characterized (13), but little is known regarding the function of ␣9␣10 nAChRs in other tissues. Here we demonstrate that the highly selective antagonist of ␣9␣10 nAChRs, RgIA, is analgesic and reduces migration of macrophages, lymphocytes, and acetylcholine (ACh)-producing cells into the area of nerve injury. ResultsRgIA Is Antinociceptive. Chronic constriction injury (CCI) produced mechanical hypersensitivity within 7 days of sciatic nerve ligation (Fig. 1). Paw withdrawal thresholds (PWTs) were reduced from 122 Ϯ 5 g to 26 Ϯ 5 g 7 days after CCI. The i.m. administration of the ␣9␣10-selective Conus peptide, RgIA, increased...

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Section: Discussionmentioning

confidence: 85%

Section: Vc1mentioning

confidence: 78%

Molecular mechanism for analgesia involving specific antagonism of α9α10 nicotinic acetylcholine receptors

Vincler

Wittenauer

Parker

et al. 2006

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

213

264

View full text Add to dashboard Cite

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“…Early studies suggested that interaction with 3 subunit-containing nAChRs may mediate these actions (Livett et al 2006), but the affinity of Vc1.1 and AuIB for these subtypes is rather weak (Clark et al 2006;Vincler et al 2006). Vc1.1 and RgIA are both potent antagonists of α9α10 nAChRs, suggesting this may be the anti-allodynia target (Vincler et al 2006).…”

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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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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“…Their three-dimensional structures incorporate an ␣-helix centered around Cys III (4), and they are regarded as rigid molecular frameworks based on their well defined secondary structure and disulfide bracing (5). ␣-Conotoxins have a range of potential therapeutic applications, including the treatment of pain and disease states such as Parkinson disease (6,7). nAChRs comprise five subunits and a range of different receptor subtypes exist depending on the subunit composition of the pentamer (8,9).…”

mentioning

confidence: 99%

“…Electrophysiological studies have shown that RgIA and Vc1.1 inhibit N-type Ca 2ϩ channel currents in dorsal root ganglion (DRG) neurons and Ca v 2.2 channels expressed in Xenopus oocytes via activation of the G protein-coupled GABA B receptor (13,20). The fact that the post-translationally modified version of Vc1.1 (Vc1a), which has Pro-6 hydroxylated and Glu-14 in loop 2 converted to a ␥-carboxyglutamic acid, is a potent inhibitor of the ␣9␣10 nAChR subtype but does not have analgesic activity (7,21) suggests that GABA B activation is responsible for the analgesic activity. Furthermore, Vc1.1 reversal of mechanical allodynia is antagonized by pretreatment with the orally active GABA B receptor antagonist SCH50911 (22 are required to resolve the precise mechanism of action of RgIA and Vc1.1 that underlies their analgesic activity.…”

mentioning

confidence: 99%

Structure and Activity of α-Conotoxin PeIA at Nicotinic Acetylcholine Receptor Subtypes and GABAB Receptor-coupled N-type Calcium Channels

Daly

Callaghan

Clark

et al. 2011

Journal of Biological Chemistry

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␣-Conotoxins are peptides from cone snails that target the nicotinic acetylcholine receptor (nAChR). RgIA and Vc1.1 have analgesic activity in animal pain models. Both peptides target the ␣9␣10 nAChR and inhibit N-type calcium channels via GABA B receptor activation, but the mechanism of action of analgesic activity is unknown. PeIA has previously been shown to inhibit the ␣9␣10 and ␣3␤2 nAChRs. In this study, we have determined the structure of PeIA and shown that it is also a potent inhibitor of N-type calcium channels via GABA B receptor activation. The characteristic ␣-conotoxin fold is present in PeIA, but it has a different distribution of surface-exposed hydrophobic and charged residues compared with Vc1.1. Thus, the surface residue distribution, rather than the overall fold, appears to be responsible for the 50-fold increase in selectivity at the ␣3␤2 nAChR by PeIA relative to Vc1.1. In contrast to their difference in potency at the nAChR, the equipotent activity of PeIA and Vc1.1 at the GABA B receptor suggests that the GABA B receptor is more tolerant to changes in surface residues than is the nAChR. The conserved Asp-Pro-Arg motif of Vc1.1 and RgIA, which is crucial for potency at the ␣9␣10 nAChR, is not required for activity at GABA B receptor/N-type calcium channels because PeIA has a His-Pro-Ala motif in the equivalent position. This study shows that different structure-activity relationships are associated with the targeting of the GABA B receptor versus nAChRs. Furthermore, there is probably a much more diverse range of conotoxins that target the GABA B receptor than currently realized.

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Therapeutic applications of conotoxins that target the neuronal nicotinic acetylcholine receptor

Cited by 123 publications

References 102 publications

Molecular mechanism for analgesia involving specific antagonism of α9α10 nicotinic acetylcholine receptors

Molecular mechanism for analgesia involving specific antagonism of α9α10 nicotinic acetylcholine receptors

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

Structure and Activity of α-Conotoxin PeIA at Nicotinic Acetylcholine Receptor Subtypes and GABAB Receptor-coupled N-type Calcium Channels

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