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The effects of pharmacological blockade of the 5-HT6 receptor on formalin-evoked nociceptive behaviour, locomotor activity and hypothalamo–pituitary–adrenal axis activity in rats

https://doi.org/10.1016/j.ejphar.2007.05.020Get rights and content

Abstract

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 hypothalamo–pituitary–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.

Introduction

The 5-HT6 receptor is a G-protein coupled receptor which is positively linked to adenylyl cyclase and expressed almost exclusively in the central nervous system (for review see Branchek and Blackburn, 2000, Woolley et al., 2004). Given the extensive expression of the 5-HT6 receptor in the basal ganglia and limbic system, much attention has focused on its potential role in psychotic disorders (Monsma et al., 1993, Roth et al., 1994, Tsai et al., 1999), affective disorders (Vogt et al., 2000, Yau et al., 1997) and in cognitive function (Lindner et al., 2003, Mitchell and Neumaier, 2005).

The distribution of the 5-HT6 receptor and/or its mRNA in regions such as the cortex, amygdala, thalamus, periaqueductal grey, spinal cord and dorsal root ganglia is also consistent with a potential role in pain and modulation of nociceptive behaviour. There is evidence of a role for 5-HT in all of these regions during nociception and analgesia (Bartsch et al., 2004, Borszcz, 1999, Del Mar et al., 1994, Plaznik et al., 1985). Moreover, many drugs used clinically to treat painful conditions including neuropathic pain and migrane exert effects on the serotonergic system and/or 5-HT receptors. There is, however, a paucity of studies investigating the role of 5-HT6 receptors in nociception which we sought to address. Given the localization of 5-HT6 receptors in the hypothalamus, the importance of 5-HT in regulation of hypothalamo–pituitary–adrenal (HPA) axis activity (for review see Dinan, 1996, Lowry, 2002) and the relationship between HPA axis activity and analgesia (Bogdanov and Yarushkina, 2000, Bomholt et al., 2004, Finn et al., 2006, MacLennan et al., 1982, Vissers et al., 2004), we also investigated 5-HT6 receptor-mediated alterations in circulating levels of plasma corticosterone which accompany alterations in nociceptive behaviour.

The aim of the present study was to use the selective 5-HT6 receptor antagonist, SB-271046, to investigate the hypothesis that 5-HT6 receptors play a role in modulating nociceptive behaviour in the rat formalin test of tonic persistent pain and associated alterations in HPA axis activity. SB-271046 is a piperazinylbenzenesulphonamide compound and a potent, brain penetrant, competitive antagonist with high affinity and selectivity for the 5-HT6 receptor (Bromidge et al., 1999, Routledge et al., 2000). The effects of SB-271046 on locomotor activity were also examined to determine the extent to which effects on formalin-evoked behaviour may represent specific effects on nociceptive behaviour per se.

Section snippets

Animals

Adult male Lister-hooded rats (250–300 g, Charles River, UK) were group housed in cages of 4 for a minimum of 5 days prior to experimentation. Rats were kept on a 12 hr light–dark cycle (lights on at 07.00 hrs) and food and water were available ad libitum. All experiments were carried out in the light period between 09:00 and 16:00 hrs according to the UK Home Office Animals (Scientific Procedures) Act 1986 under Project Licence number 40/1955 and in accordance with the ethical guidelines of

Results

Intraplantar injection of formalin produced robust licking, flinching, shaking and elevation of the right hindpaw. The early phase (3–8 min) and late phase (13–58 min) marked two distinct periods of formalin-evoked nociceptive behaviour (measured as CPS) in vehicle-treated rats (Fig. 1). Two-way ANOVA revealed a significant effect of treatment (F3, 231 = 4.43; P = 0.005), time (F10, 231 = 36.26; P < 0.0001) and a significant treatment × time interaction (F30, 231 = 1.84; P = 0.007) on formalin-evoked

Discussion

The present study is the first to demonstrate a potential role for 5-HT6 receptors in modulation of nociceptive behaviour. To date, there has been only one other published report on the role of 5-HT6 receptors in nociception (Bourson et al., 1995). This study investigated the effects of repeated intracerebroventricular administration of an antisense oligonucleotide sequence, designed to block translation of 5-HT6 mRNA, on acute nociception assessed using the hot plate test in rats. Despite a

Acknowledgement

The authors wish to thank F. Hoffman La Roche Ltd, Basel, Switzerland for supplying the 5-HT6 receptor antagonist, SB-271046.

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