Involvement of calcitonin gene-related peptide and its receptor in anti- nociception in the periaqueductal grey of rats Long-Chuan Yu a,b, * , Xing-He Weng a , Jing-Wen Wang a , Thomas Lundeberg b a Laboratory of Neurobiology, College of Life Sciences, National Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing 100871, China b Department of Physiology and Pharmacology, and Department of Medical Rehabilitation, Karolinska Institutet, 171 77 Stockholm, Sweden Received 13 December 2002; received in revised form 17 February 2003; accepted 18 February 2003 Abstract The present study investigated the role of calcitonin gene-related peptide (CGRP) in the modulation of nociception in periaqueductal grey (PAG) of rats. Hindpaw withdrawal latencies (HWLs) were tested by hot-plate and Randall Selitto tests. The HWLs to thermal and mechanical stimulation increased significantly after intra-PAG administration of 0.26 or 0.13 nmol of CGRP, but not 0.026 nmol of CGRP. The anti-nociceptive effects induced by CGRP were significantly blocked by intra-PAG administration of 0.026 or 0.26 nmol of the CGRP1 receptor antagonist CGRP8-37. Furthermore, administration of CGRP into the decussation of superior cerebellar peduncle, out of PAG, did not elicit anti-nociceptive effects during 60 min after the injection. The results demonstrated that CGRP plays an important role in anti- nociception in PAG of rats, and CGRP1 receptor is involved in the CGRP-induced anti-nociception. q 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Calcitonin gene-related peptide; CGRP8-37; CGRP1 receptor; Periaqueductal grey; Hindpaw withdrawal latency; Anti-nociception Calcitonin gene-related peptide (CGRP) is a 37 amino acid neuropeptide, which is widely distributed in the nerve system and has multiple physiological functions [4,7,12,15]. It has been demonstrated that CGRP plays an important role in pain modulation [2,5,6,11,18,20]. Intrathecal injection of CGRP8-37, a selective antagonist of CGRP1 receptor, induced anti-nociceptive effect in intact rats, rats with inflammation and rats with mononeuropathy [17–19]. Intracerebroventricular injection of CGRP produced an anti-nociceptive effect in rats and mice [2,11]. Recent study in our laboratory demonstrated that CGRP produced anti- nociceptive effects in the nucleus raphe magnus of rats [5]. Periaqueductal grey (PAG) is one of the most important brain structures involved in the endogenous anti-nociceptive system [1,3,8]. Smith and collaborators reported that there are many neurotransmitters and neuropeptides that exist in PAG, including CGRP [14]. The present study was performed to explore the effect of CGRP on the modulation of nociception in PAG of rats. All experiments were performed on freely moving male Sprague–Dawley rats (200–300 g; Experimental Animal Center of Peking University, Beijing, China). The rats were housed in cages with free access to food and water, and maintained in a room temperature of 24 ^ 2 8C with a 12 h light/dark cycle. All experiments were conducted according to the guidelines of the Animal Ethical Committee of Karolinska Institutet and every effort was made to minimize animal suffering. Rats were anaesthetized by intraperitoneal pentobarbital (40 mg/kg) and were mounted on a stereotaxic instrument. A stainless steel guide cannula of 0.8 mm out- diameter was directed to the PAG (AP 5.5, L 0.5, H 6.0 mm from the surface of the skull) according to Paxinos and Watson [10] and was fixed to the skull by dental acrylic. On the experimental day a stainless steel needle with 0.4 mm diameter was inserted directly into the guide cannula, with 1 mm beyond the tip of the latter. Thereafter 1 ml of solution was infused into PAG over 1 min. Rats were accustomed to the nociceptive test conditions for 5 days before the experiment was conducted. The latencies to left hindpaw withdrawal during thermal and mechanical stimulation were measured. The thermal response was assessed by the hot-plate. The entire ventral 0304-3940/03/$ - see front matter q 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0304-3940(03)00273-8 Neuroscience Letters 349 (2003) 1–4 www.elsevier.com/locate/neulet * Corresponding author. College of Life Sciences, Peking University, Beijing 100871, China. Tel.: þ86-10-62762099; fax: þ86-10-62751526. E-mail address: yulc@pku.edu.cn (L.C. Yu).