title: Multiple impairments of cutaneous nociceptor function induced by cardiotoxic doses of Adriamycin in the rat.
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.
authors.affiliation: Department of Physiology, University of Szeged, Dóm tér 10, Szeged, H-6720, Hungary.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Boros
authors.affiliation: Department of Physiology, University of Szeged, Dóm tér 10, Szeged, H-6720, Hungary. gaborjancso@yahoo.co.uk.
authors.forename: Gábor
authors.initials: G
authors.lastname: Jancsó
authors.affiliation: Department of Physiology, University of Szeged, Dóm tér 10, Szeged, H-6720, Hungary.
authors.forename: Mária
authors.initials: M
authors.lastname: Dux
authors.affiliation: Department of Anatomy, University of Szeged, Kossuth L. Sgt. 40, Szeged, H-6724, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Fekécs
authors.affiliation: Department of Biochemistry, University of Szeged, Dóm tér 9, Szeged, H-6720, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Bencsik
authors.affiliation: Department of Physiology, University of Szeged, Dóm tér 10, Szeged, H-6720, Hungary.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Oszlács
authors.affiliation: Department of Pediatrics and Pediatric Health Center, University of Szeged, Korányi fasor 14-15, Szeged, H-6720, Hungary.
authors.forename: Márta
authors.initials: M
authors.lastname: Katona
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4, Budapest, H-1089, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Ferdinandy
authors.affiliation: Department of Anatomy, University of Szeged, Kossuth L. Sgt. 40, Szeged, H-6724, Hungary.
authors.forename: Antal
authors.initials: A
authors.lastname: Nógrádi
authors.affiliation: Department of Physiology, University of Szeged, Dóm tér 10, Szeged, H-6720, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Sántha
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology; D066126:Cardiotoxicity; D002351:Carrageenan; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity*; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009149:Mustard Plant; D059225:Nociception / Q000187:drug effects*; D010938:Plant Oils / Q000494:pharmacology; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism; D012867:Skin / Q000098:blood supply / Q000294:innervation*; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000819:agonists / Q000378:metabolism; D050916:TRPV Cation Channels / Q000819:agonists / Q000378:metabolism; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D015415:Biomarkers; D010938:Plant Oils; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050916:TRPV Cation Channels; C480976:Trpa1 protein, rat; C493922:Trpv1 protein, rat; D004317:Doxorubicin; D002351:Carrageenan; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin; C027793:mustard oil
keywords: Adriamycin; Cardioprotection; Chemosensitive primary sensory neuron; Chemotherapy-induced neurotoxicity; Cutaneous innervation; Sensory neuropeptides