Phα1β toxin prevents capsaicin-induced nociceptive behavior and mechanical hypersensitivity without acting on TRPV1 channels

Castro, Célio José de; Milano, Julie; Souza, Alessandra Hübner de; Silva, Juliana F.; Rigo, Flávia Karine; Dalmolin, Gerusa Duarte; Cordeiro, Marta N.; Richardson, Michael; Barros, A.G.A.; Gomez, Renato Santiago; Silva, Marco A.R.; Kushmerick, Christopher; Ferreira, Juliano; Gomez, Marcus V.

doi:10.1016/j.neuropharm.2013.04.001

Cited by 31 publications

(27 citation statements)

References 44 publications

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“…It has been already shown that the state of tolerance to self as well as oral tolerance to fed antigens is concomitant to a highly immune activated state (116, 117). Indeed auto-reactive antibodies as well as auto-reactive T lymphocytes can be found in healthy individuals.…”

Section: Gut Microbiota–host Interactions and Oral Tolerance: When Thmentioning

confidence: 99%

Towards a Liquid Self: How Time, Geography, and Life Experiences Reshape the Biological Identity

et al. 2014

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The conceptualization of immunological self is amongst the most important theories of modern biology, representing a sort of theoretical guideline for experimental immunologists, in order to understand how host constituents are ignored by the immune system (IS). A consistent advancement in this field has been represented by the danger/damage theory and its subsequent refinements, which at present represents the most comprehensive conceptualization of immunological self. Here, we present the new hypothesis of “liquid self,” which integrates and extends the danger/damage theory. The main novelty of the liquid self hypothesis lies in the full integration of the immune response mechanisms into the host body’s ecosystems, i.e., in adding the temporal, as well as the geographical/evolutionary and environmental, dimensions, which we suggested to call “immunological biography.” Our hypothesis takes into account the important biological changes occurring with time (age) in the IS (including immunosenescence and inflammaging), as well as changes in the organismal context related to nutrition, lifestyle, and geography (populations). We argue that such temporal and geographical dimensions impinge upon, and continuously reshape, the antigenicity of physical entities (molecules, cells, bacteria, viruses), making them switching between “self” and “non-self” states in a dynamical, “liquid” fashion. Particular attention is devoted to oral tolerance and gut microbiota, as well as to a new potential source of unexpected self epitopes produced by proteasome splicing. Finally, our framework allows the set up of a variety of testable predictions, the most straightforward suggesting that the immune responses to defined molecules representing potentials antigens will be quantitatively and qualitatively quite different according to the immuno-biographical background of the host.

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Section: Gut Microbiota–host Interactions and Oral Tolerance: When Thmentioning

confidence: 99%

Towards a Liquid Self: How Time, Geography, and Life Experiences Reshape the Biological Identity

et al. 2014

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“…Some animal venoms contain substances that target TRP channels, including APHC1, which antagonizes TRPV1, and the tarantula venom peptide, ProTx‐I, which inhibits TRPA1 channels (Andreev et al, ; Gui et al, ). Phα1β was found to reduce nociceptive responses evoked by capsaicin administration (Castro‐Junior et al, ). Notably, the reduction was obtained by using very high local doses of the toxin, while in vitro 2 μM Phα1β failed to inhibit TRPV1 channels.…”

Section: Introductionmentioning

confidence: 99%

The peptide Phα1β, from spider venom, acts as a TRPA1 channel antagonist with antinociceptive effects in mice

Tonello

Fusi

Materazzi

et al. 2016

British J Pharmacology

Self Cite

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BACKGROUND AND PURPOSEPeptides from venomous animals have long been important for understanding pain mechanisms and for the discovery of pain treatments. Here, we hypothesized that Phα1β, a peptide from the venom of the armed spider Phoneutria nigriventer, produces analgesia by blocking the TRPA1 channel. EXPERIMENTAL APPROACHCultured rat dorsal root ganglion (DRG) neurons, human fetal lung fibroblasts (IMR90) or HEK293 cells expressing the human TRPA1 (hTRPA1-HEK293), human TRPV1 (hTRPV1-HEK293) or human TRPV4 channels (hTRPV4-HEK293), were used for calcium imaging and electrophysiology. Nociceptive responses induced by TRPA1, TRPV1 or TRPV4 agonists or by bortezomib were investigated in mice. KEY RESULTSPhα1β selectively inhibited calcium responses and currents evoked by the TRPA1 agonist, allyl isothiocyanate (AITC), on hTRPA1-HEK293, IMR90 fibroblasts and DRG neurons. Phα1β did not affect calcium responses evoked by selective TRPV1 (capsaicin) or TRPV4 (GSK 1016790A) agonists on the various cell types. Intrathecal (i.t.) and intraplantar (i.pl.) administration of low doses of Phα1β (up to 300 pmol per paw) attenuated acute nociception and mechanical and cold hyperalgesia evoked by AITC (i.t. or i.pl.), without affecting responses produced by capsaicin or hypotonic solution. Notably, Phα1β abated the TRPA1-dependent neuropathic pain-like responses induced by bortezomib. In vitro and in vivo inhibition of TRPA1 by Phα1β was reproduced by a recombinant form of the peptide, CTK 01512-2. CONCLUSIONS AND IMPLICATIONSPhα1β and CTK 01512-2 selectively target TRPA1, but not other TRP channels. This specific action underlines the potential of Phα1β and CTK 01512-2 for pain treatment.Abbreviations AITC, allyl isothiocyanate; BTZ, bortezomib; CIPN, chemotherapy-induced peripheral neuropathy; DRG, dorsal root ganglia; i.pl., intraplantar; IMR90, human fetal lung fibroblasts; PWT, paw withdrawal threshold; VGCCs, voltage-gated calcium channels

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“…Thus, native and recombinant toxins increased DNA damage in spinal cord, the target tissue of these toxins, but not in peripheral blood, suggesting selective‐tissue DNA damage which may be implicated in their action mechanism on neurotransmission systems. In fact, these toxins have different antinociceptive effects when compared with ω‐CTx‐MVIIA, which have been explained due to diverse actions on N‐type VGCC or due to inhibition on other VGCC such as R‐type, P/Q‐type and L‐type . In addition, Phα1β and CTK 01512‐2 have shown antagonism on TRPA1 channels, besides acting on VGCC, which may increase not only their antinociceptive effects, but also their adverse reaction .…”

Section: Resultsmentioning

confidence: 99%

“…N‐type VSCC are widely found in spinal cord neurons and control the release of neurotransmitters, playing an important role in the ascending peripheral pain to the brain . Some studies have shown that Phα1β toxin has antinociceptive action in several rodent pain models, showing effects on acute and persistent pain, including visceral, neuropathic, inflammatory, surgical and cancer pains …”

Section: Introductionmentioning

confidence: 99%

Evaluation of DNA damage in spinal cord and mutagenic effect of a Phα1β recombinant toxin with analgesic properties from the Phoneutria nigriventer spider

Souza

Rosa

Uliano

et al. 2018

Basic Clin Pharma Tox

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Phα1β peptide isolated from the venom of the Phoneutria nigriventer spider has shown higher analgesic action in pre-clinical studies than ω-conotoxin MVIIA peptide used to treat severe chronic pain. In view of the great potential for the development of a new Phα1β-based drug, a Phα1β recombinant form (CTK 01512-2) has been studied for efficacy and safety. The aim of this study was to evaluate cytotoxic, genotoxic and mutagenic effects of a Phα1β recombinant form and compare it with native Phα1β and ω-conotoxin MVIIA. Cytotoxicity was evaluated using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) colourimetric assay in L929 mouse fibroblast cells (0.5-10.0 μmol/L). Genotoxic and mutagenic activities were analysed using the alkaline comet assay in peripheral blood and spinal cord, and the micronucleus test in bone marrow from Wistar rats treated by intrathecal injection of CTK 01512-2 (200, 500 and 1000 pmol/site), native Phα1β (500 pmol/site) and ω-conotoxin MVIIA (200 pmol/site). CTK 01512-2 decreased the cell viability of the L929, showing IC 50 of 3.3 ± 0.1 µmol/L, while the Phα1β and ω-conotoxin MVIIA did not show cytotoxicity (IC 50 > 5.0 µmol/L). Native and recombinant Phα1β forms induced DNA damage in the spinal cord, but not in peripheral blood. CTK 01512-2 at 1000 pmol/site increased the micronucleus frequency suggesting mutagenic effects. In conclusion, the recombinant form has cytotoxic, genotoxic and mutagenic effects, evidenced in doses five times above the therapeutic dose. K E Y W O R D S comet assay, cytotoxicity, DNA damage, micronucleus, Phα1β, toxins

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Phα1β toxin prevents capsaicin-induced nociceptive behavior and mechanical hypersensitivity without acting on TRPV1 channels

Cited by 31 publications

References 44 publications

Towards a Liquid Self: How Time, Geography, and Life Experiences Reshape the Biological Identity

Towards a Liquid Self: How Time, Geography, and Life Experiences Reshape the Biological Identity

The peptide Phα1β, from spider venom, acts as a TRPA1 channel antagonist with antinociceptive effects in mice

Evaluation of DNA damage in spinal cord and mutagenic effect of a Phα1β recombinant toxin with analgesic properties from the Phoneutria nigriventer spider

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