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

Abstract

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.Neuromedin U (NMU) is a highly conserved neuropeptide, present in various species from amphibians to mammals (reviewed in reference 3). In humans, NMU is a 25-amino-acid (aa) peptide (NMU-25), and in rodents, it is a 23-aa peptide (NMU-23), whereas in some other mammalian species an 8-aa peptide (NMU-8) has also been found. NMU-8 is identical to the C terminus of NMU-25, which is the most highly conserved region of the entire peptide, and has receptor affinity in vitro similar to that of NMU-25. NMU is widely distributed in the body, with the most abundant expression in the gastrointestinal tract, anterior pituitary, spinal cord, brain, and genitourinary tract (6, 42). Correspondingly, NMU has been implicated in regulating a variety of physiological functions, including smooth-muscle contraction, blood pressure regulation, stress response, feeding and energy homeostasis, nociception, and circadian rhythm (reviewed in reference 3).Two G-protein-coupled receptors, NMUR1 and NMUR2, have been identified as the receptors for NMU (8,18,20,21,37,41,42). The two receptors belong to the rhodopsin-like class A G-protein-coupled receptors family and share ϳ50% identity with each other in the seven-transmembrane region. The tissue distribution of the two receptors is quite distinct and complementary to each other: NMUR1 is expressed predominantly in the periphery, with highest levels in the gastrointestinal tract (8,10,18,42), whereas NMUR2 is predominantly expressed in the central nervous system, with greatest expression in regions of hypothalamus, medulla, and spinal cord (9,10,14,20,21,41).In the brain, NMU is expressed in hypothalamic regions associated with regulation of food intake and energy homeostasi...

Comparison of feeding suppression by the anorexigenic hormones neuromedin U and neuromedin S in rats

“…In addition, it is also unclear why NMU KO mice develop obesity (Hanada et al 2004), whereas NMUR2 KO mice are lean and smaller than normal (Zeng et al 2006, Novak 2009, Peier et al 2009). Of course, as mentioned above, NMS may act on an undefined receptor other than NMU1R and NMU2R.…”

“…Evidence accumulated over the last decade has suggested that NMU and/or NMS are involved in the central regulation of feeding, energy homeostasis, stress, and circadian rhythms, probably through NMUR2 , Hanada et al 2001, Ivanov et al 2002, Nakahara et al 2004a,b, Ida et al 2005, Novak et al 2006, Zeng et al 2006, Novak 2009, Peier et al 2009). I.c.v.…”

The Kisspeptin Receptor GPR54 Is Required for Sexual Differentiation of the Brain and Behavior

“…GPR54 KO mice were produced by retroviral mutagenesis as described previously (Krasnow et al, 2004;Zeng et al, 2006). Briefly, an embryonic stem (ES) cell library was constructed by infecting 129/Sv ES cells with a retroviral vector that included a selection marker, termination codons in all reading frames, a splice adaptor, and a transcription terminator to ensure gene inactivation after insertion.…”

Role of G protein-coupled receptors in inflammation

“…In addition to the NK1 receptor, the neuromedin U2 receptor (NMU2) plays a central role in nociception. NMU2 knockout mice display reduced sensitivity to pain induced by capsaicin and formalin [46] .…”