Role of central endothelin-1 in hyperalgesia, anhedonia, and hypolocomotion induced by endotoxin in male rats

• Published in: Experimental brain research 2021, Vol.239 (1), p.267-277
• Main Authors: Lomba, Luís Alexandre, Cruz, Juliana Varella, Coelho, Letícia Costa Mastrangelo, Leite-Avalca, Mariane Cristina Guttervill, Correia, Diego, Zampronio, Aleksander Roberto
• Format: Article
• Language: English
• Subjects: Anhedonia; Animals; Biomedical and Life Sciences; Biomedicine; Brain research; Care and treatment; Causes of; Central nervous system; Development and progression; Endothelin; Endothelin 1; Endothelin ETB receptors; Endotoxins; Fever; Health aspects; Hedonic response; Hyperalgesia; Hypothalamus; Inflammation; Lipopolysaccharides; Locomotor activity; Nervous system; Neurology; Neurosciences; Pain; Pain perception; Peptides; Physiological aspects; Prostaglandin endoperoxide synthase; Research Article; Sucrose
• ISSN: 0014-4819; 1432-1106
• DOI: 10.1007/s00221-020-05929-1

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 ET A and ET B 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 ET A receptor antagonist BQ123 and exacerbated by the ET B 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 ET A receptors in the hypothalamus also abolished lipopolysaccharide-induced mechanical hyperalgesia, and the ET B 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 ET A and ET B receptors are involved in various responses that are related to sickness syndrome, including hyperalgesia, anhedonia, and hypolocomotion, that is induced by LPS. Hypothalamic ET A but not ET B receptors are involved in mechanical hyperalgesia that is observed during lipopolysaccharide-induced sickness syndrome.