Alpha-conotoxin Vc1.1 alleviates neuropathic pain and accelerates functional recovery of injured neurones

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

doi:10.1016/j.brainres.2005.08.009

Cited by 172 publications

(199 citation statements)

References 37 publications

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“…Our results demonstrate that RgIA, a highly selective antagonist of the ␣9␣10 nAChR, produces an acute antinociceptive effect in peripheral nerve-injured rats similar to that previously reported for Vc1.1 (14). More importantly, repeated daily administration of this nAChR antagonist produced a stable decrease in injury-induced mechanical hypersensitivity.…”

Section: Discussionsupporting

confidence: 88%

“…Consistent with previous reports (14), i.m. administration of 0.036 g (0.018 nmol) or 0.36 g (0.18 nmol) of Vc1.1 in CCI rats produced 34 Ϯ 18% and 89 Ϯ 20% increases in PWTs, respectively (data not shown).…”

Section: Vc1supporting

confidence: 94%

“…After 7 days of repeated Vc1.1 administration, baseline PWTs (measured 24 h after Vc1.1 administration) were significantly increased by 61 Ϯ 4% (0.36-g dose) and 13 Ϯ 7% (0.036-g dose) compared with pretreatment values for Vc1.1. This decrease in injury-induced mechanical hypersensitivity is consistent with the observations of Satkunanathan et al (14).…”

Section: Vc1supporting

confidence: 93%

“…Although it is generally nAChR agonists that are reported to be analgesic, ␣-conotoxin Vc1.1, also known as ACV1, a compound in human clinical trials by Metabolic (Melbourne, Australia), is a nAChR antagonist that previously has been shown to be analgesic. Peripheral application of this peptide blocks the vascular inflammatory response to electrical stimulation of C fibers and is analgesic in CCI and partial nerve ligation models of human neuropathic pain (14,15). The previously reported subtype specificity of this analgesic peptide is for ␣3(␣5)␤2 and ␣3(␣5)␤4 nAChRs with micromolar IC 50 values (16).…”

Section: Vc1mentioning

confidence: 89%

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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: Discussionsupporting

confidence: 88%

Section: Vc1supporting

confidence: 94%

Section: Vc1supporting

confidence: 93%

Section: Vc1mentioning

confidence: 89%

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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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“…The α-conotoxins represent one such family that specifically target nicotinic acetylcholine receptor (nAChR) subtypes. Owing to the combination of a large variety of nAChR subunit assemblies and subunit-selective α-conotoxins, many potential novel analgesics have recently been identified (Dutton and Craik 2001;Alonso et al 2003;Sandall et al 2003;Lang et al 2005;Satkunanathan et al 2005;Olivera et al 2008;McIntosh et al 2009) α-Conotoxins, including Vc1.1, RgIA, MII and AuIB, have all been reported to potently reverse signs of neuropathic pain, particularly tactile allodynia, in animal models when administered systemically (Satkunanathan et al 2005;Klimis et al 2011).…”

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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Nicotinic acetylcholine receptors in neuropathic and inflammatory pain

2017

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Edited by Wilhelm JustNicotinic acetylcholine receptors (nAChRs) are actively being investigated as therapeutic targets for the treatment of pain and inflammation, but despite more than 30 years of research, there are currently no FDA-approved analgesics that are specific for these receptors. Much of the initial research effort focused on the a4b2 nAChR subtype, but more recently, additional subtypes have been identified as promising new leads and include a6b4, a7, and a9-containing nAChRs. This Review will focus on the distribution of these nAChRs in the cell types involved in neuropathic pain and inflammation and the activity of currently available nicotinic ligands.

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Alpha-conotoxin Vc1.1 alleviates neuropathic pain and accelerates functional recovery of injured neurones

Cited by 172 publications

References 37 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

Nicotinic acetylcholine receptors in neuropathic and inflammatory pain

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