Neuroscience Letters 416 (2007) 123–127 The peripheral role of group I metabotropic glutamate receptors on nociceptive behaviors in rats with knee joint inflammation Kyu Sang Lee 1 , Junesun Kim 1 , Young Wook Yoon, Min-Goo Lee, Seung Kil Hong, Hee Chul Han ∗ Department of Physiology, Brain Korea 21 Project for Medical Science, College of Medicine and Neuroscience Research Institute, Korea University, 126–1 Anam-dong 5 ga, Sungbuk-gu, Seoul 136–705, South Korea Received 8 December 2006; received in revised form 20 January 2007; accepted 29 January 2007 Abstract We examined whether the mGluR1 and mGluR5 were involved in development and maintenance of behavioral signs of non-evoked pain and secondary mechanical hyperalgesia induced by knee joint inflammation. Selective mGluR1 antagonist, (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA: 50, 100, 200 M/25 l, n = 10 per group) and selective mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP: 50, 100, 200 nM/25 l, n = 10 per group) was intra-articularly (i.a.) injected 30 min before and 4 h after carrageenan injection and behavioral tests were conducted. In the pre-treatment, only a higher dose (200 nM) of MPEP significantly prevented the magnitude of weight load reduction, whereas AIDA (200 M) and MEPE (50, 100 and 200 nM) significantly reduced the development of mechanical hyperalgesia compared to saline treated group. In the post-treatment, AIDA (200 M) and MPEP at 100 and 200 nM partially reversed the reduction of weight load induced by carrageenan. MPEP significantly increased the withdrawal threshold to mechanical stimulation in a dose-dependent manner, whereas AIDA had significantly reversed the decreased the paw withdrawal threshold only at 200 M. The present study demonstrated that i.a. MPEP, selective mGluR5 antagonist is more effective than selective mGluR1 antagonist, AIDA on non-evoked pain as well as mechanical hyperalgesia in both induction and maintenance phase in knee joint inflammation. It is suggested that peripheral mGlu5 receptors play a more prominent role in inflammatory pain including evoked and spontaneous pain. Thus, selective mGluR5 antagonist could be effective therapeutic tools in clinical setting. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Arthritis; Carrageenan; Metabotropic glutamate receptors; mGluR; Inflammatory pain; Weight bearing Inflammation produces painful sensations which are largely divided into spontaneous (non-evoked) pain and evoked pain depending on the presence of external stimuli and are characterized by hyperalgesia and allodynia resulting both from sensitization of peripheral receptors and the spinal dorsal horn neurons [12]. Glutamate concentration increases in the spinal dorsal horn after inflammation, which is one of several factors that may account for sensitization [20,21]. Glutamate binds to both ligand-gated ion channels (ionotropic glutamate receptors, iGluRs) and G protein-coupled receptor types (metabotropic glutamate receptors, mGluRs) [4,14]. mGluRs, in particular Group I mGluRs (mGluR1 and mGluR5), have been recognized ∗ Corresponding author. Tel.: +82 2 920 6186; fax: +82 2 925 5492. E-mail address: heehan@korea.ac.kr (H.C. Han). 1 These authors equally contribute to the present work. to play a role in nociceptive processing [15] but most studies on the function of mGluRs in nociception have focused on the spinal cord [8,17,16]. Recently, a few studies have demonstrated that the peripheral group I mGluRs also participate in nociceptive processing [1,2,23,24]. Moreover, the respective roles of sub- types 1 and 5, which belong to group I mGluRs, are less clear [24,28]. For example, the mechanical hyperalgesia developed in the Freund’s complete adjuvant model of inflammatory pain was blocked by a selective mGluR5 antagonist [24] but ther- mal hyperalgesia produced by kaolin and carrageenan injection was reversed more selectively by an mGluR1 antagonist [26]. It is still not clear whether mGluR1 and mGluR5 are related to spontaneous (non-evoked) pain processing in the knee joint inflammation model. The present study was performed to investigate the contri- bution of group I mGluRs to development and maintenance of behavioral signs of spontaneous (non-evoked) pain and mechan- ical hyperalgesia induced by knee joint inflammation. 0304-3940/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2007.01.063