Role of central endothelin-1 in hyperalgesia, anhedonia, and hypolocomotion induced by endotoxin in male rats
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RESEARCH ARTICLE
Role of central endothelin‑1 in hyperalgesia, anhedonia, and hypolocomotion induced by endotoxin in male rats Luís Alexandre Lomba1 · Juliana Varella Cruz1 · Letícia Costa Mastrangelo Coelho1 · Mariane Cristina Guttervill Leite‑Avalca1 · Diego Correia1 · Aleksander Roberto Zampronio1 Received: 9 July 2020 / Accepted: 16 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Sickness syndrome is an adaptive response that can be distinguished by specific signs and symptoms, such as fever and generalized hyperalgesia. Endothelin-1 (ET-1) is produced by inflammatory stimuli, including lipopolysaccharide, and involved in the pathogenesis of inflammation and pain by acting through E TA and ETB receptors. ET-1 also induces fever by acting on the central nervous system. The present study investigated the role of ET-1 in sickness syndrome responses, including hyperalgesia, anhedonia, and hypolocomotion. Intracerebroventricular ET-1 administration induced mechanical and thermal hyperalgesia in rats, which was ameliorated by the ETA receptor antagonist BQ123 and exacerbated by the ETB receptor antagonist BQ788. A cyclooxygenase blocker did not alter hyperalgesia that was induced by ET-1. Lipopolysaccharide administration induced hyperalgesia, and both BQ123 and BQ788 abolished this mechanical hyperalgesia, but the thermal response was only partially blocked. The blockade of E TA receptors in the hypothalamus also abolished lipopolysaccharideinduced mechanical hyperalgesia, and the E TB receptor antagonist did not influence this response. Lipopolysaccharide also induced anhedonia, reflected by lower sucrose preference, and reduced locomotor activity. Both antagonists restored locomotor activity, but only BQ788 reversed the reduction of sucrose preference. These results indicate that ET-1 and both ETA and ETB receptors are involved in various responses that are related to sickness syndrome, including hyperalgesia, anhedonia, and hypolocomotion, that is induced by LPS. Hypothalamic E TA but not E TB receptors are involved in mechanical hyperalgesia that is observed during lipopolysaccharide-induced sickness syndrome. Keywords Endothelin-1 · Lipopolysaccharide · Hypothalamus · Hyperalgesia · Sickness behavior
Introduction Most people experience such symptoms as fever, hyperalgesia, and prostration during an acute episode of infection. These symptoms are called sickness syndrome, and the related behaviors are referred to as sickness behaviors. These behavioral, endocrine, and autonomic changes are adaptive Communicated by Bill J Yates. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00221-020-05929-1) contains supplementary material, which is available to authorized users. * Aleksander Roberto Zampronio [email protected] 1
Department of Pharmacology, Federal University of Paraná, Centro Politécnico, PO Box 19031, Curitiba, PR 81531‑980, Brazil
responses that are regulated by the central nervous system (CNS) t
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