A role for orexin in cytotoxic chemotherapy-induced fatigue

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41 Scopus citations


Fatigue is the most common symptom related to cytotoxic chemotherapeutic treatment of cancer. Peripheral inflammation associated with cytotoxic chemotherapy is likely a causal factor of fatigue. The neural mechanisms by which cytotoxic chemotherapy associated inflammation induces fatigue behavior are not known. This lack of knowledge hinders development of interventions to reduce or prevent this disabling symptom. Infection induced fatigue/lethargy in rodents is mediated by suppression of hypothalamic orexin activity. Orexin is critical for maintaining wakefulness and motivated behavior. Though there are differences between infection and cytotoxic chemotherapy in some symptoms, both induce peripheral inflammation and fatigue. Based on these similarities we hypothesized that cytotoxic chemotherapy induces fatigue by disrupting orexin neuron activity. We found that a single dose of a cytotoxic chemotherapy cocktail (cyclophosphamide, adriamycin, 5-fluorouracil - CAF) induced fatigue/lethargy in mice and rats as evidenced by a significant decline in voluntary locomotor activity measured by telemetry. CAF induced inflammatory gene expression - IL-1R1 (p<. 0.001), IL-6 (p<. 0.01), TNFα (p<. 0.01), and MCP-1 (p<. 0.05) - in the rodent hypothalamus 6-24. h after treatment during maximum fatigue/lethargy. CAF decreased orexin neuron activity as reflected by decreased nuclear cFos localization in orexin neurons 24. h after treatment (p<. 0.05) and by decreased orexin-A in cerebrospinal fluid 16. h after treatment (p<. 0.001). Most importantly, we found that central administration of1. μg orexin-A restored activity in CAF-treated rats (p<. 0.05). These results demonstrate that cytotoxic chemotherapy induces hypothalamic inflammation and that suppression of hypothalamic orexin neuron activity has a causal role in cytotoxic chemotherapy-induced fatigue in rodents.

Original languageEnglish (US)
Pages (from-to)84-94
Number of pages11
JournalBrain, Behavior, and Immunity
StatePublished - Mar 2014


  • Activity
  • Cancer treatment
  • Cytotoxic chemotherapy
  • Fatigue
  • Hypothalamus
  • Inflammation
  • Orexin
  • Sickness behavior
  • Wakefulness

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience


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