Research report Comparison of mice deficient in the high- or low-affinity neurotensin receptors, Ntsr1 or Ntsr2, reveals a novel function for Ntsr2 in thermal nociception Hiroshi Maeno a, * , Kazuyuki Yamada a,b , Yuko Santo-Yamada a,c , Kumiko Aoki a , Ying-Jie Sun a,1 , Eiichi Sato a , Tatsuo Fukushima d , Hiroo Ogura d , Tsutomu Araki e , Sari Kamichi a,f , Ichiro Kimura f , Mariko Yamano g , Yuka Maeno-Hikichi a,2 , Kei Watase a,3 , Shunsuke Aoki a , Hiroshi Kiyama h , Etsuko Wada a, * , Keiji Wada a a Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8502, Japan b Advanced Technology Development Group, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan c Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan d Discovery Research Laboratories I, Eisai Co., Ltd., 1-3 Tokodai, 5-chome, Tsukuba, Ibaraki 300-2635, Japan e Department of Drug Metabolism and Therapeutics, Graduate School and Faculty of Pharmaceutical Sciences, The University of Tokushima, 1-78 Sho-machi, Tokushima 770-8505, Japan f Department of Cell Biology, School of Human Sciences, Waseda University, 2-579-15 Mikajima, Tokorozawa, Saitama 359-1192, Japan g Department of Rehabilitation, Osaka Prefecture College of Nursing, Habikino, 3-7-30, Osaka 583-8555, Japan h Department of Anatomy, Graduate School of Medicine, Osaka City University, Asahimachi, Abenoku, Osaka 545-8585, Japan Accepted 21 November 2003 Abstract Neurotensin (NT) is a neuropeptide that induces a wide range of biological activities including hypothermia and analgesia. Such effects are mediated by the NT receptors Ntsr1, Ntsr2 and Ntsr3, although the involvement of each receptor in specific NT functions remains unknown. To address nociceptive function in vivo, we generated both Ntsr1-deficient and Ntsr2-deficient mice. In addition, histochemical analyses of both Ntsr1 and Ntsr2 mRNAs were performed in the mouse brain regions involved in NT-related nociception. The expression of Ntsr2 mRNAwas greater than that of Ntsr1 in the periaqueductal gray (PAG) and the rostral ventral medulla (RVM). The mutant and control mice were subjected to the examination of thermal nociception, and in the hot plate test, a significant alteration in jump latency was observed in Ntsr2-deficient mice compared to Ntsr1-deficient or wild-type control mice. Latencies of tail flick and hind paw licking of the mutant mice were not affected compared to control mice. These results suggest that Ntsr2 has an important role in thermal nociception compared to Ntsr1, and that these mutant mice may represent a useful tool for the development of analgesic drugs. D 2003 Elsevier B.V. All rights reserved. Theme: Neurotransmitters, modulators, transporters, and receptors Topic: Peptide receptor structure and function Keywords: Neurotensin receptor; Homologous recombination; Hot plate test; Tail flick test; Nociception; In situ hybridization 0006-8993/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2003.11.039 * Corresponding authors. Tel: +81-42-346-1715; fax: +81-42-346-1745. E-mail addresses: maeno@ncnp.go.jp (H. Maeno), wada _ e@ncnp.go.jp (E. Wada). 1 Current address: Department of Anatomy, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. 2 Current address: Department of Molecular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musasidai, Fuchu, Tokyo 183-0042, Japan. 3 Current address: Department of Molecular and Human Genetics and Howard Hughes Medical Institute, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA. www.elsevier.com/locate/brainres Brain Research 998 (2004) 122 – 129