A Novel α-Conotoxin Identified by Gene Sequencing Is Active in Suppressing the Vascular Response to Selective Stimulation of Sensory Nerves in Vivo

Sandall, David; Satkunanathan, Narmatha; Keays, David A.; Polidano, M.; Liping, X.; Pham, Vi; Down, J. G.; Khalil, Zeinab; Livett, Bruce G.; Gayler, Kenwyn R.

doi:10.1021/bi034043e

Cited by 178 publications

(167 citation statements)

References 24 publications

(45 reference statements)

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“…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: 90%

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: Vc1mentioning

confidence: 90%

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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“…Among these nAChRs, the a7-nAChRs are known to be overexpressed in small-cell lung carcinomas associated with smoking (74). Results from in vitro experiments suggest that malignant growth can be halted with the use of snake neurotoxins (a-neurotoxins) or snail conotoxins (a-conotoxins) (75,76) because they are competitive antagonists of a7-nAChR (77). In vivo animal studies have further shown that a7-nAChR inhibitors, such as MLA (78,79) and a-Bgtx (80), can reverse the proangiogenic effects of nicotine and inhibit cancer cell growth (16,17,19,81,82).…”

Section: Nachr Antagonists As Potential Agents For Molecular Cancer Tmentioning

confidence: 99%

Nicotinic Acetylcholine Receptor-Based Blockade: Applications of Molecular Targets for Cancer Therapy

Lee

2011

Clinical Cancer Research

103

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The nicotinic acetylcholine receptor (nAChR) was first characterized in 1970 as a membrane receptor of a neurotransmitter and an ion channel. nAChRs have been shown to be involved in smoking-induced cancer formation in multiple types of human cancer cells. In vitro and in vivo animal studies have shown that homopentameric nAChR inhibitors, such as methyllycaconitine and a-Bgtx, can attenuate nicotine-induced proliferative, angiogenic, and metastatic effects in lung, colon, and bladder cancer cells. Recent publications have shown that a9-nAChR is important for breast cancer formation, and in many in vivo studies, a9-nAChR-specific antagonists (e.g., a-ImI, a-ImI, Vc1.1, RgIA, and It14a) produced an analgesic effect. Vc1.1 functions in a variety of animal pain models and currently has entered phase II clinical trials. For cancer therapy, natural compounds such as garcinol and EGCG have been found to block nicotine-and estrogeninduced breast cancer cell proliferation through inhibition of the a9-nAChR signaling pathway. A detailed investigation of the carcinogenic effects of nAChRs and their specific antagonists would enhance our understanding of their value as targets for clinical translation.

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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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A Novel α-Conotoxin Identified by Gene Sequencing Is Active in Suppressing the Vascular Response to Selective Stimulation of Sensory Nerves in Vivo

Cited by 178 publications

References 24 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

Nicotinic Acetylcholine Receptor-Based Blockade: Applications of Molecular Targets for Cancer Therapy

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

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