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The Journal of Neuroscience, July 30, 2008, 28(31):7728-7736; doi:10.1523/JNEUROSCI.1480-08.2008

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Behavioral/Systems/Cognitive
Activation of the β-Adrenoceptor–Protein Kinase A Signaling Pathway within the Ventral Bed Nucleus of the Stria Terminalis Mediates the Negative Affective Component of Pain in Rats

Satoshi Deyama,^1,2 Takahiro Katayama,¹ Atsushi Ohno,¹ Takayuki Nakagawa,² Shuji Kaneko,² Taku Yamaguchi,³ Mitsuhiro Yoshioka,³ and Masabumi Minami¹

¹Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan, ²Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan, and ³Deparment of Neuropharmacology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan

Correspondence should be addressed to Dr. Masabumi Minami, Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan. Email: mminami{at}pharm.hokudai.ac.jp

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 its affective component. The bed nucleus of the stria terminalis (BNST) has been implicated in stress responses and negative affective states, such as anxiety, fear, and aversion. Recently, we demonstrated the crucial role of the BNST in the negative affective component of pain using the conditioned place aversion (CPA) test. In the present study, we investigated the involvement of the β-adrenoceptor–protein kinase A (PKA) signaling pathway within the BNST, in particular, within the ventral part of the BNST (vBNST), in pain-induced aversion in male Sprague Dawley rats. In vivo microdialysis showed that extracellular noradrenaline levels within the vBNST were significantly increased by intraplantar formalin injection. Using the CPA test, we found that intra-vBNST injection of timolol, a β-adrenoceptor antagonist, dose-dependently attenuated the intraplantar-formalin-induced CPA (F-CPA) without reducing nociceptive behaviors. Experiments with subtype-selective antagonists demonstrated the essential role of β₂-adrenoceptors in F-CPA. Intra-vBNST injection of isoproterenol, a β-adrenoceptor agonist, dose-dependently produced CPA even in the absence of noxious stimulation. This isoproterenol-induced CPA was reversed by the coinjection of Rp-cyclic adenosine monophosphorothioate (Rp-cAMPS), a selective PKA inhibitor. Furthermore, intra-vBNST injection of Rp-cAMPS dose-dependently attenuated the F-CPA. Together, these results suggest that PKA activation within the vBNST via the enhancement of β-adrenergic transmission is important for the negative affective component of pain.

Key words: bed nucleus of the stria terminalis; conditioned place aversion; emotion; noradrenaline; protein kinase A; pain

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Received Dec. 13, 2007; revised May 12, 2008; accepted June 18, 2008.

Correspondence should be addressed to Dr. Masabumi Minami, Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan. Email: mminami{at}pharm.hokudai.ac.jp

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