Multiple impairments of cutaneous nociceptor function induced by cardiotoxic doses of Adriamycin in the rat

Krisztina Boros, G. Jancsó, M. Dux, Zoltán Fekécs, Péter Bencsik, Orsolya Oszlács, M. Katona, P. Ferdinándy, Antal Nógrádi, P. Sántha

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Abstract

Besides their deleterious action on cardiac muscle, anthracycline-type cytostatic agents exert significant neurotoxic effects on primary sensory neurons. Since cardiac sensory nerves confer protective effects on heart muscle and share common traits with cutaneous chemosensitive nerves, this study examined the effects of cardiotoxic doses of adriamycin on the function and morphology of epidermal nerves. Sensory neurogenic vasodilatation, plasma extravasation, and the neural CGRP release evoked by TRPV1 and TRPA1 agonists in vitro were examined by using laser Doppler flowmetry, the Evans blue technique, and ELISA, respectively. Carrageenan-induced hyperalgesia was assessed with the Hargreaves method. Immunohistochemistry was utilized to study cutaneous innervation. Adriamycin treatment resulted in profound reductions in the cutaneous neurogenic sensory vasodilatation and plasma extravasation evoked by the TRPV1 and TRPA1 agonists capsaicin and mustard oil, respectively. The in vitro capsaicin-, but not high potassium-evoked neural release of the major sensory neuropeptide, CGRP, was markedly attenuated after adriamycin treatment. Carrageenan-induced inflammatory hyperalgesia was largely abolished following the administration of adriamycin. Immunohistochemistry revealed a substantial loss of epidermal TRPV1-expressing nociceptive nerves and a marked thinning of the epidermis. These findings indicate impairments in the functions of TRPV1 and TRPA1 receptors expressed on cutaneous chemosensitive nociceptive nerves and the loss of epidermal axons following the administration of cardiotoxic doses of adriamycin. Monitoring of the cutaneous nociceptor function in the course of adriamycin therapy may well be of predictive value for early detection of the deterioration of cardiac nerves which confer protection against the deleterious effects of the drug.

Original languageEnglish
Pages (from-to)1-12
Number of pages12
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
DOIs
Publication statusAccepted/In press - Jun 24 2016

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Nociceptors
Doxorubicin
Skin
Carrageenan
Capsaicin
Hyperalgesia
Vasodilation
Myocardium
Immunohistochemistry
Evans Blue
Laser-Doppler Flowmetry
Anthracyclines
Cytostatic Agents
Sensory Receptor Cells
Neuropeptides
Epidermis
Axons
Potassium
Therapeutics
Enzyme-Linked Immunosorbent Assay

Keywords

  • Adriamycin
  • Cardioprotection
  • Chemosensitive primary sensory neuron
  • Chemotherapy-induced neurotoxicity
  • Cutaneous innervation
  • Sensory neuropeptides

ASJC Scopus subject areas

  • Pharmacology

Cite this

Multiple impairments of cutaneous nociceptor function induced by cardiotoxic doses of Adriamycin in the rat. / Boros, Krisztina; Jancsó, G.; Dux, M.; Fekécs, Zoltán; Bencsik, Péter; Oszlács, Orsolya; Katona, M.; Ferdinándy, P.; Nógrádi, Antal; Sántha, P.

In: Naunyn-Schmiedeberg's Archives of Pharmacology, 24.06.2016, p. 1-12.

Research output: Contribution to journalArticle

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abstract = "Besides their deleterious action on cardiac muscle, anthracycline-type cytostatic agents exert significant neurotoxic effects on primary sensory neurons. Since cardiac sensory nerves confer protective effects on heart muscle and share common traits with cutaneous chemosensitive nerves, this study examined the effects of cardiotoxic doses of adriamycin on the function and morphology of epidermal nerves. Sensory neurogenic vasodilatation, plasma extravasation, and the neural CGRP release evoked by TRPV1 and TRPA1 agonists in vitro were examined by using laser Doppler flowmetry, the Evans blue technique, and ELISA, respectively. Carrageenan-induced hyperalgesia was assessed with the Hargreaves method. Immunohistochemistry was utilized to study cutaneous innervation. Adriamycin treatment resulted in profound reductions in the cutaneous neurogenic sensory vasodilatation and plasma extravasation evoked by the TRPV1 and TRPA1 agonists capsaicin and mustard oil, respectively. The in vitro capsaicin-, but not high potassium-evoked neural release of the major sensory neuropeptide, CGRP, was markedly attenuated after adriamycin treatment. Carrageenan-induced inflammatory hyperalgesia was largely abolished following the administration of adriamycin. Immunohistochemistry revealed a substantial loss of epidermal TRPV1-expressing nociceptive nerves and a marked thinning of the epidermis. These findings indicate impairments in the functions of TRPV1 and TRPA1 receptors expressed on cutaneous chemosensitive nociceptive nerves and the loss of epidermal axons following the administration of cardiotoxic doses of adriamycin. Monitoring of the cutaneous nociceptor function in the course of adriamycin therapy may well be of predictive value for early detection of the deterioration of cardiac nerves which confer protection against the deleterious effects of the drug.",
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AU - Dux, M.

AU - Fekécs, Zoltán

AU - Bencsik, Péter

AU - Oszlács, Orsolya

AU - Katona, M.

AU - Ferdinándy, P.

AU - Nógrádi, Antal

AU - Sántha, P.

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