Altered Nociceptive Response in Mice Deficient in the  1B Subunit of the Voltage-Dependent Calcium Channel Chanki Kim, 1 Kisun Jun,* ,1 Taehoon Lee, Sung-Sook Kim, Maureen W. McEnery, † Hemin Chin, ‡ Hyung-Lae Kim, § Joo Min Park, ¶ Dong Kwan Kim, ¶ Sung Jun Jung,  Jun Kim, ¶ and Hee-Sup Shin 2 National CRI Center for Calcium and Learning and Department of Life Science, Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, 790-784, Korea; *College of Medicine, Pochon CHA University, CHA General Hospital, Seoul, Korea; † Department of Physiology and Biophysics, and Neuroscience, Case Western Reserve University, Cleveland, Ohio; ‡ Genetics Research Branch, Division of Neuroscience and Basic Behavioral Science, NIH, Bethesda, Maryland; § Department of Biochemistry, Medical College, Ewha Womans University, Seoul, Korea; ¶ Department of Physiology and Biophysics, Seoul National University College of Medicine, Seoul, Korea; and Department of Physiology, Dankook University College of Medicine, Chunan, Korea Calcium influx through N-type calcium channels mediates synaptic transmission at numerous central synapses and transduces nociceptive information in the spinal dorsal horn. However, the precise role of N-type calcium chan- nels in pain perception is not fully elucidated. To address this issue, we generated and analyzed knockout mice for  1B, the pore-forming subunit of the N-type calcium chan- nel. Homozygous mutants are viable, fertile, and show normal motor coordination. In small-diameter dorsal root ganglion neurons from mutants the density of calcium channel currents is significantly reduced, which can be accounted for by the abolition of N-type currents. We performed several pain-related behavioral tests using the mutant mice.  1B -Deficient mice show reduced response to mechanical stimuli in the von Frey test and increased tail flick latency in response to radiant heat, indicating altered spinal reflexes. However, pain response in the hot plate test is normal. In the formalin paw test, the mutant mice exhibit significantly attenuated response in Phase 2, but normal pain behaviors in Phase 1. The response to visceral inflammatory pain caused by acetic acid is also reduced in  1B knockout mice. These results suggest that the  1B subunit of N-type calcium channel plays a major role in pain perception by acting at the spinal level, but not at the supraspinal level. INTRODUCTION There are many different kinds of voltage-dependent calcium channels (VDCC) that play important roles in the control of neurotransmitter release, membrane ex- citability, and gene expression (Catterall, 1998). These channels have multi-subunit structures consisting of a major pore-forming subunit,  1 , and several ancillary subunits (Dunlap et al., 1995; De Waard et al., 1996; Hofmann et al., 1999). At least six different genes ( 1B –  1F ) have been identified to encode different isotypes of the  1 subunits (Chin, 1998; Ertel et al., 2000; Hofmann et al., 1999). The  1B subunit that comprises the N-type calcium channel was originally cloned and sequenced from rat brains (Dubel et al., 1992). In situ hybridization in adult rat brains has shown that  1B is widely distrib- uted in various regions of the brain, especially in the hippocampal CA regions, dentate gyrus, and cerebellar granule cell layer (Tanaka et al., 1995). At the subcellular level,  1B is highly localized at the presynaptic nerve terminals of most neurons, consistent with its physio- 1 These two authors contributed equally to this work. 2 To whom correspondence and reprint requests should be ad- dressed at Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul, 130-650 Korea. Fax: +82-2-958-6919. E-mail: shin@kist.re.kr. Molecular and Cellular Neuroscience 18, 235–245 (2001) doi:10.1006/mcne.2001.1013, available online at http://www.idealibrary.com on MCN 1044-7431/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved. 235