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5-HT3 receptor antagonists ameliorate fatigue: so much potential, so little knowledge!
  1. N M Barnes
  1. Correspondence to:
    Dr N M Barnes
    Cellular and Molecular Neuropharmacology Research Group, Department of Pharmacology, Division of Neuroscience, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK;

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There is growing evidence that 5-HT3 receptor blockade will benefit patients with fatigue. Further research is needed to determine the mechanism underlying this widespread clinically important symptom and therapies may be derived from targeting the 5-HT system

Despite a high prevalence with massive socioeconomic implications, fatigue per se, or as a symptom of a diagnosed condition, remains poorly understood. Much of the evidence available arises from measurement of biochemicals or proteins; alterations in which may be primary or secondary to the symptom, or indeed associated with another aspect of an underlying disease. However, an increasing body of evidence implicates an altered central 5-HT (5-hydroxytryptamine; serotonin) system. Although apparent inconsistencies are evident (for example, see Hartz and colleagues1), elevated 5-HT neurotransmission appears most likely.2–5 Numerous distinct receptors have evolved to transduce 5-HT signalling. The majority of these receptors (at least 13) are G protein coupled receptors (GPCRs) but, unusual for monoamine neurotransmitters, an additional receptor, the 5-HT3 receptor, is a member of the cys-cys loop ligand gated ion channel superfamily; other members being the nicotinic acetylcholine receptor, the GABAA receptor, and the glycine receptor.6 The 5-HT3 receptor is predominantly expressed by central neurones and peripheral nerves and is known to mediate fast synaptic neurotransmission in the brain.

The clinical availability of 5-HT3 receptor antagonists offers an opportunity to probe further for roles for this receptor. In …

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  • Conflict of interest: None declared.

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