An antinociceptive role of galanin in the arcuate nucleus of hypothalamus in intact rats and rats with inflammation Yan-Gang Sun a , Xing-Long Gu a , Thomas Lundeberg b , Long-Chuan Yu a, * a Neurobiology Laboratory, College of Life Sciences, National Laboratory of Biomembrane and Membrane Biotechnology and Center for Brain and Cognitive Science, Peking University, Beijing 100871, China b Department of Physiology, and Pharmacology, and Department of Medical Rehabilitation, Karolinska Institutet, 171 77 Stockholm, Sweden Received 20 January 2003; received in revised form 21 July 2003; accepted 29 July 2003 Abstract In the arcuate nucleus of hypothalamus (ARC), galaninergic fibers form synaptic contacts with proopiomelanocortin neurons, which are involved in pain modulation. The present study assessed the role of exogenous and endogenous galanin in the modulation of nociception in the ARC of rats. The hindpaw withdrawal latency (HWL) to thermal and mechanical stimulation was assessed by the hot-plate test and the Randall Selitto Test. Intra-ARC injection of galanin dose-dependently increased the HWLs in intact rats, indicating an antinociceptive role of exogenous galanin in the ARC. The antinociceptive effect of galanin was blocked by following intra-ARC injection of galantide, a putative galanin receptor antagonist, suggesting that the antinociceptive effect of galanin is mediated by galanin receptors. Moreover, intra-ARC injection of galanin increased the HWL in rats with inflammation. Intra-ARC administration of galantide alone reduced the HWLs in rats with inflammation, while there were no influences of galantide on the HWL in intact rats. Taken together, the results show that galanin has an antinociceptive role in the ARC of intact rats and rats with inflammation. q 2003 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. Keywords: Arcuate nucleus; Inflammation; Galanin; Galanin receptors; Antinociception; Hyperalgesia 1. Introduction The neuropeptide galanin was first isolated in 1983 in the laboratory of Mutt (Tatemoto et al., 1983). Galanin is proteolytically processed from a large precursor protein; it appears to be a unique sequence unrelated to any other known family of peptides. In most mammals, galanin consists of 29 amino acids, which is conserved in the N- terminal between species (Iismaa and Shine, 1999). Three galanin receptor subtypes have been cloned and all of them are G-protein coupled receptors (Branchek et al., 2000). There are wide distributions of galanin and galanin receptors in the central nervous system (Bedecs et al., 1995; Melander et al., 1986; Merchenthaler et al., 1993; Skofitsch and Jacobowitz, 1986). Galanin has been shown to be involved in a variety of physiological processes (Gundlach, 2002; Rajendren, 2002; Wiesenfeld-Hallin and Xu, 2001). Previous studies have demonstrated that galanin is upregulated after nerve injury or inflammation (Colvin et al., 1997; Ma and Bisby, 1997), suggesting an involvement of galanin in pain processing. The role of galanin in nociception has been investigated using behavioral (Liu and Hokfelt, 2000; Wang et al., 2000) and electrophysiological techniques (Flatters et al., 2002; Xu et al., 2000; Yu et al., 2001). We have demonstrated that galanin microinjected into the midbrain periaqueductal gray matter (PAG) of intact and mononeuropathic rats induced prolonged withdrawal latencies (Wang et al., 1999, 2000). A role of galanin in nociception during inflammation has been suggested, but the results have been contradictory (Heppel- mann et al., 2000; Wiesenfeld-Hallin and Xu, 2001). It has been reported that galanin has an antinociceptive effect during inflammation in spinalized rats (Wiesenfeld-Hallin and Xu, 2001). On the other hand, a pronociceptive action is supported by Kerr and collaborators who reported that endogenous galanin is necessary for central sensitization (Kerr et al., 2001). They suggested that galanin plays a critical role in the development of the hyperalgesia seen following peripheral tissue injury. Even if there is controversy regarding the role of exogenous galanin in inflammation, it has been clearly 0304-3959/$20.00 q 2003 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/S0304-3959(03)00316-6 Pain 106 (2003) 143–150 www.elsevier.com/locate/pain * Corresponding author. Tel.: þ86-10-6276-2099; fax: þ 86-10-6275- 1526. E-mail address: yulc@pku.edu.cn (L.-C. Yu).