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Molecular and Cellular Biology, December 2006, p. 9352-9363, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.01148-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Neuromedin U Receptor 2-Deficient Mice Display Differential Responses in Sensory Perception, Stress, and Feeding

Hongkui Zeng,^1* Alexander Gragerov,^1, John G. Hohmann,^1, Maria N. Pavlova,^1, Brian A. Schimpf,¹ Hui Xu,² Long-Jun Wu,² Hiroki Toyoda,² Ming-Gao Zhao,² Alex D. Rohde,^1, Galina Gragerova,^1, Rene Onrust,^1, John E. Bergmann,^1, Min Zhuo,² and George A. Gaitanaris^1,

Nura, Inc., 1124 Columbia Street, Seattle, Washington 98104,¹ Department of Physiology, Faculty of Medicine, University of Toronto, University of Toronto Centre for the Study of Pain, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada²

Received 26 June 2006/ Returned for modification 17 August 2006/ Accepted 22 September 2006

Neuromedin U (NMU) is a highly conserved neuropeptide with a variety of physiological functions mediated by two receptors, peripheral NMUR1 and central nervous system NMUR2. Here we report the generation and phenotypic characterization of mice deficient in the central nervous system receptor NMUR2. We show that behavioral effects, such as suppression of food intake, enhanced pain response, and excessive grooming induced by intracerebroventricular NMU administration were abolished in the NMUR2 knockout (KO) mice, establishing a causal role for NMUR2 in mediating NMU's central effects on these behaviors. In contrast to the NMU peptide-deficient mice, NMUR2 KO mice appeared normal with regard to stress, anxiety, body weight regulation, and food consumption. However, the NMUR2 KO mice showed reduced pain sensitivity in both the hot plate and formalin tests. Furthermore, facilitated excitatory synaptic transmission in spinal dorsal horn neurons, a mechanism by which NMU stimulates pain, did not occur in NMUR2 KO mice. These results provide significant insights into a functional dissection of the differential contribution of peripherally or centrally acting NMU system. They suggest that NMUR2 plays a more significant role in central pain processing than other brain functions including stress/anxiety and regulation of feeding.

Published ahead of print on 9 October 2006.

Present address: Omeros Corporation, 1124 Columbia Street, Seattle, WA 98104.

Present address: Allen Institute for Brain Science, 551 N. 34th Street, Seattle, WA 98103.

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