Elsevier

Neuropharmacology

Volume 61, Issues 1–2, July–August 2011, Pages 156-160
Neuropharmacology

Inhibition of noradrenaline release by clonidine in the ventral bed nucleus of the stria terminalis attenuates pain-induced aversion in rats

https://doi.org/10.1016/j.neuropharm.2011.03.023Get rights and content

Abstract

Pain is an unpleasant sensory and emotional experience. The neural systems underlying the sensory component of pain have been studied extensively, but we are only beginning to understand those underlying the affective component of pain. Previously, we showed the pivotal role of noradrenergic transmission in the ventral part of the bed nucleus of the stria terminalis (vBNST) in the negative affective component of pain using a conditioned place paradigm. In this study, we examined the effect of local administration of clonidine, an α2-adrenoceptor agonist, into the vBNST on noradrenaline release and on conditioned place aversion (CPA) induced by an intraplantar formalin injection in male Sprague-Dawley rats. In vivo microdialysis showed that the formalin-induced increase in the extracellular noradrenaline level within the vBNST was significantly suppressed by clonidine (100 μM) perfusion through a microdialysis probe. Bilateral intra-vBNST injections of clonidine (1 and 10 nmol/side) dose-dependently attenuated formalin-induced CPA without reducing nociceptive behaviors. These results suggest that clonidine inhibits noradrenaline release by acting on α2-adrenoceptors located in the vBNST and thereby attenuates pain-induced aversion. α2-adrenoceptors in the vBNST play a pivotal role in the regulation of negative affective, but not the sensory, component of pain.

Highlights

► Pain-induced noradrenaline release in the ventral BNST was suppressed by clonidine. ► Intra-vBNST injections of clonidine significantly attenuated pain-induced aversion. ► Intra-vBNST injections of clonidine did not affect nociceptive behaviors. ► 2-adrenoceptors in the vBNST play a pivotal role in the affective component of pain.

Introduction

Pain is a complex experience consisting of sensory and negative affective components. Although neuronal pathways and brain regions involved in the sensory component of pain have been studied extensively, neuronal systems underlying the affective component of pain remain to be elucidated. Recently, behavioral studies using a conditioned place aversion (CPA) test showed the neural substrates involved in the negative affective component of pain. Johansen et al. (2001) reported that excitotoxic lesions of the anterior cingulate cortex (ACC) suppress intraplantar formalin-induced CPA (F-CPA) without reducing formalin-induced nociceptive behaviors. We showed that the central (CeA) and basolateral (BLA) amygdaloid nuclei are involved differently in F-CPA and intraperitoneal acetic acid-induced CPA (A-CPA) (Tanimoto et al., 2003). Additionally, we reported the involvement of the bed nucleus of the stria terminalis (BNST) in the affective component of pain (Deyama et al., 2007a).

The BNST, particularly the ventral part (vBNST), is densely innervated by noradrenergic fibers arising mainly from medullary A1/A2 cell groups (Forray et al., 2000, Woulfe et al., 1990). Noradrenergic transmission within this brain area is critical for mediating negative emotions such as anxiety, fear, and aversion (Cecchi et al., 2002, Delfs et al., 2000, Fendt et al., 2005, Schweimer et al., 2005). Recently, we demonstrated the pivotal role of enhanced noradrenergic transmission within the vBNST in somatic and visceral pain-induced aversion in rats (Deyama et al., 2008, Deyama et al., 2009). α2-adrenoceptors are known to play regulatory roles in the sensory component of pain. Specifically, α2-adrenoceptor agonists, such as clonidine, produce antinociception at the spinal level (Reddy et al., 1980, Yaksh et al., 1995) at least in part through the inhibitory effect on glutamate release from the primary afferent terminal (Ueda et al., 1995). However, the roles of α2-adrenoceptors in the affective component of pain remain unclear. Therefore, in this study, we investigated the effects of local administrations of clonidine into the vBNST on intraplantar formalin-induced noradrenaline release and on F-CPA.

Section snippets

Animals

Male Sprague-Dawley rats (200–240 g; Japan SLC, Hamamatsu, Japan) were used. The rats were housed four per cage. Following implantation surgery of the guide cannulae, the rats were individually housed in cages. The rats were maintained at a constant ambient temperature (22 ± 1 °C) under a 12-h light/dark cycle with food and water available ad libitum. All experiments were approved by the institutional animal care and use committee of Hokkaido University and conformed to the guidelines of the

Effect of clonidine on formalin-induced noradrenaline release within the vBNST

In the normal Ringer’s solution-perfused control group, an intraplantar injection of formalin produced an increase in extracellular noradrenaline levels within the vBNST as we previously reported (Deyama et al., 2008) (Fig. 2). Perfusion of clonidine (100 μM) via the microdialysis probe suppressed this increase. Two-way repeated-measures ANOVA demonstrated a significant effect between the clonidine- and normal Ringer’s solution-perfused rats (F1, 22 = 28.9, P < 0.001) and a significant

Discussion

We previously demonstrated that excitotoxic lesions of the BNST abolished F-CPA and A-CPA without reducing nociceptive behaviors (Deyama et al., 2007a). Additionally, we reported that enhanced noradrenergic transmission via β-adrenoceptors within the vBNST mediates pain-induced aversion (Deyama et al., 2008, Deyama et al., 2009). Our current study using an in vivo microdialysis technique and a CPA test extends those findings by showing that inhibition of intra-vBNST noradrenaline release by

Acknowledgements

This study was supported by grants from the Hoansha Foundation (M.M.) and Astellas Foundation for Research on Metabolic Disorders (M.M.).

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