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Systemic, Intrathecal, and Intracerebroventricular Antihyperalgesic Effects of the Calcium Channel Blocker CTK 01512–2 Toxin in Persistent Pain Models

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Abstract

CTK 01512–2 toxin is a recombinant peptide of the Phα1β version derived from the venom of the Phoneutria nigriventer spider. It acts as an N-type voltage-gated calcium channel (VGCC) blocker and shows a prolonged effect on preventing and reducing nociception. Herein, CTK 01512–2 was tested on two models of persistent pain, the chronic post-ischemia pain (CPIP) and the paclitaxel-induced peripheral neuropathy, to evaluate its systemic, intrathecal, and intracerebroventricular effects on mechanical hypersensitivity and thermal allodynia. Glial cell viability was also investigated using the MTT test. The results showed that CTK 01512–2 intrathecal and systemic treatments reduced the mechanical hypersensitivity induced by CPIP, mainly between 1–4 h after its administration. Additionally, intrathecal treatment reduced the CPIP-induced thermal allodynia. In its turn, the intracerebroventricular treatment showed mechanical antihyperalgesic and thermal antiallodynic effects in the paclitaxel-induced peripheral neuropathy. These data reinforce the therapeutic potential of CTK 01512–2 to treat persistent pain conditions and offer a perspective to use the systemic route. Moreover, CTK 01512–2 increased the glial cell viability in the MTT reduction assay, and it may indicate a new approach to managing chronic pain. The results found in this study help to pave new perspectives of pain relief treatments to patients affected by chronic pain.

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

CRPS-I:

Complex regional pain syndrome-type I

CPIP:

Chronic post-ischemia pain

IR:

Ischemia and reperfusion

TRP:

Transient receptor potential channel

LAIF:

Laboratory of Autoimmunity and Immunopharmacology

CEUA:

Committee on Ethics in the Use of Animals

ANOVA:

Analysis of variance

ARRIVE:

Animal Research: Reporting in vivo Experiments

CNS:

Central nervous system

IL:

Interleukin

CONCEA:

Brazilian Council of Animal Experimentation

g:

Grams

h:

Hours

i.p.:

Intraperitoneal

kg:

Kilograms

mg:

Milligrams

min:

Minutes

ml:

Milliliters

PTX:

Paclitaxel

PWT:

Paw withdrawal threshold

SEM:

Standard error of mean

mmol:

Millimolar

UFSC:

Universidade Federal de Santa Catarina

AUC:

Area under the curve

μl:

Microliters

LPS:

Lipopolysaccharide

CGRP:

Calcitonin gene-related peptide

MTT:

Methyl-thiazolyl diphenyl-tetrazolium bromide

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Acknowledgements

We thank the Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Universidade Federal de Santa Catarina (UFSC), Programa de Pós-Graduação em Neurociências (PPGNEURO/UFSC), and Programa INCT-INOVAMED (grant 465430/2014-7), all from Brazil.

Funding

E.C.D.G. and P.M.A are Ph.D. student in the Neuroscience and Health Program, respectively, receiving grants from the CAPES/FAPESC. A.Q.S., M.V.G., and R.C.D. are recipients of a research productivity fellowship from the CNPq.

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Authors and Affiliations

  1. Laboratório de Autoimunidade E Imunofarmacologia, Departamento de Ciências da Saúde, Universidade Federal de Santa Catarina, Campus Araranguá, Araranguá, SC, 88906-072, Brazil

    Juliana Cavalli, Elaine Cristina Dalazen Gonçalves & Rafael Cypriano Dutra

  2. Núcleo de Pesquisa E Inovação Em Ciências da Saúde, Faculdade de Farmácia, Universidade Federal de Juiz de Fora, Juiz de Fora, MG, 36036-330, Brazil

    Pollyana Mendonça de Assis

  3. Programa de Pós-Graduação Em Neurociências, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil

    Elaine Cristina Dalazen Gonçalves & Rafael Cypriano Dutra

  4. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, 90035-003, Brazil

    Larissa Daniele Bobermin & André Quincozes-Santos

  5. Núcleo de Pós-Graduação, Instituto de Ensino E Pesquisa da Santa Casa de Belo Horizonte, Belo Horizonte, MG, 30150-240, Brazil

    Nádia Rezende Barbosa Raposo & Marcus Vinicius Gomez

Authors
  1. Juliana Cavalli
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  2. Pollyana Mendonça de Assis
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  5. André Quincozes-Santos
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  8. Rafael Cypriano Dutra
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Contributions

Study design and concept, and manuscript writing: JC, PMA, ECDG, LDB, AQS, RCD; experiment implementation and manuscript drafting: JC, PMA, ECDG, LDB, AQS, RCD; figure production: JC, PMA, RCD; data analysis: JC, LDB, AQS, RCD; experiment support: JC, ECDG, LDB, AQS, RCD; the manuscript draft was critically revised by JC, LDB, AQS, NRBR, MVG, RCD. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Rafael Cypriano Dutra.

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Ethics Approval and Consent to Participate

The manuscript does not contain clinical studies or patient data. The Animal Ethics Committee approved all procedures in this study involving animals of the Universidade Federal de Santa Catarina (CEUA/UFSC, protocol number 3914220319). All of the experimental procedures were conducted according to the guidelines of CONCEA and CEUA/UFSC, based on the principles of the 3Rs (Replacement, Reduction, and Refinement).

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Cavalli, J., de Assis, P.M., Cristina Dalazen Gonçalves, E. et al. Systemic, Intrathecal, and Intracerebroventricular Antihyperalgesic Effects of the Calcium Channel Blocker CTK 01512–2 Toxin in Persistent Pain Models. Mol Neurobiol 59, 4436–4452 (2022). https://doi.org/10.1007/s12035-022-02864-w

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