Are alpha9alpha10 nicotinic acetylcholine receptors a pain target for alpha-conotoxins?

The synthetic alpha-conotoxin Vc1.1 is a small disulfide bonded peptide currently in development as a treatment for neuropathic pain. Unlike Vc1.1, the native post-translationally modified peptide vc1a does not act as an analgesic in vivo in rat models of neuropathic pain. It has recently been proposed that the primary target of Vc1.1 is the alpha9alpha10 nicotinic acetylcholine receptor (nAChR). We show that Vc1.1 and its post-translationally modified analogs vc1a, [P6O]Vc1.1, and [E14?]Vc1.1 are equally potent at inhibiting ACh-evoked currents mediated by alpha9alpha10 nAChRs. This suggests that alpha9alpha10 nAChRs are unlikely to be the molecular mechanism or therapeutic target of Vc1.1 for the treatment of neuropathic pain

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

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 a-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 a-conotoxins. Intrathecal administration of a-conotoxins, Vc1.1, AuIB and MII into neuropathic rats reduced mechanical allodynia for up to 6 h 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 a3, a7 or other subunits. Intrathecal nAChR subunit-selective conotoxins are therefore promising tools for the effective treatment of neuropathic pain

Are alpha 9 alpha 10 nicotinic acetylcholine receptors a pain target for alpha-conotoxins?

The synthetic alpha-conotoxin Vc1.1 is a small disulfide bonded peptide currently in development as a treatment for neuropathic pain. Unlike Vc1.1, the native post-translationally modified peptide vc1a does not act as an analgesic in vivo in rat models of neuropathic pain. It has recently been proposed that the primary target of Vc1.1 is the alpha 9 alpha 10 nicotinic acetylcholine receptor (nAChR). We show that Vc1.1 and its post-translationally modified analogs vc1a, [P6O]Vc1.1, and [E14 gamma]Vc1.1 are equally potent at inhibiting ACh-evoked currents mediated by alpha 9 alpha 10 nAChRs. This suggests that alpha 9 alpha 10 nAChRs are unlikely to be the molecular mechanism or therapeutic target of Vc1.1 for the treatment of neuropathic pain

Lowbush wild blueberries have the potential to modify gut microbiota and xenobiotic metabolism in the rat colon.

The gastrointestinal tract is populated by an array of microbial species that play an important role in metabolic and immune functions. The composition of microorganisms is influenced by the components of the host's diet and can impact health. In the present study, dietary enrichment of lowbush wild blueberries (LWB) was examined to determine their effect on colon microbial composition and their potential in promoting gut health. The microbial composition and functional potential of the colon microbiota from Sprague Dawley rats fed control diets (AIN93) and LWB-enriched diets (AIN93+8% LWB powder substituting for dextrose) for 6 weeks were assessed using Illumina shotgun sequencing and bioinformatics tools. Our analysis revealed an alteration in the relative abundance of 3 phyla and 22 genera as representing approximately 14 and 8% of all phyla and genera identified, respectively. The LWB-enriched diet resulted in a significant reduction in the relative abundance of the genera Lactobacillus and Enterococcus. In addition, hierarchal analysis revealed a significant increase in the relative abundance of the phylum Actinobacteria, the order Actinomycetales, and several novel genera under the family Bifidobacteriaceae and Coriobacteriaceae, in the LWB group. Functional annotation of the shotgun sequences suggested that approximately 9% of the 4709 Kyoto Encyclopaedia of Gene and Genome (KEGG) hits identified were impacted by the LWB-diet. Open Reading Frames (ORFs) assigned to KEGG category xenobiotics biodegradation and metabolism were significantly greater in the LWB-enriched diet compared to the control and included the pathway for benzoate degradation [PATH:ko00362] and glycosaminoglycan degradation [PATH:ko00531]. Moreover, the number of ORFs assigned to the bacterial invasion of epithelial cells [PATH:ko05100] pathway was approximately 8 fold lower in the LWB group compared to controls. This study demonstrated that LWBs have the potential to promote gut health and can aid in the development of optimal diets

Vertical Specialization and New Determinants of FDI: Evidence from South and East Asia

By estimating a dynamic panel-gravity model of bilateral foreign direcr investment (FDI), this article investigates the location determinants of inward FDI in South and East Asia and assesses their short-run and long-run effects. The econometric results highlight the importance of the vertical specialization-, trade-, and international integration-related location factors. The gravity-specific variables are also found to be significant location determinants, whilst some of the traditional determinants are found to have either a weak or statistically insignificant effect (except host-market size) on inward FDI in South and East Asia.Foreign direct investment (FDI), vertical specialization links, location determinants, South &East Asia, international economic integration,

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

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 alpha-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 alpha-conotoxins. Intrathecal administration of alpha-conotoxins, Vc1.1, AuIB and MII into neuropathic rats reduced mechanical allodynia for up to 6 h 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 alpha 3, alpha 7 or other subunits. Intrathecal nAChR subunit-selective conotoxins are therefore promising tools for the effective treatment of neuropathic pain. (C) 2012 Elsevier Ltd. All rights reserved