5-hydroxytryptamine (5-HT) mediates behavioural and neuroendocrine responses to noxious or stressful stimuli. 5-HT6 receptors are expressed in brain regions involved in nociceptive processing, however, their role in nociception is unknown. Here we demonstrate that acute, systemic administration of the 5-HT6 receptor antagonist, 5-chloro-N-(4-methoxy-3-benzothio-phenesulfonamide (SB-271046), reduces formalin-evoked nociceptive behaviour and increases plasma corticosterone. SB-271046 dose-dependently reduced pre-formalin distance moved, rearing, grooming and defecation. These data provide the first evidence for 5-HT6 receptor-mediated regulation of nociception and hypothalamopituitary-adrenal axis activity in a model of persistent pain although effects on locomotor activity demand that the putative antinociceptive effect of SB-271046 be interpreted with some caution. (c) 2007 Elsevier B.V. All rights reserved.