Mice genetically deficient in neuromedin U receptor 2, but not neuromedin U receptor 1, have impaired nociceptive responses

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Pain (Impact Factor: 5.84). 09/2007; 130(3):267-78. DOI: 10.1016/j.pain.2007.01.036
Source: PubMed

ABSTRACT Neuromedin U (NMU) has recently been reported to have a role in nociception and inflammation. To clarify the function of the two known NMU receptors, NMU receptor 1 (NMUR1) and NMU receptor 2 (NMUR2), during nociception and inflammation in vivo, we generated mice in which the genes for each receptor were independently deleted. Compared to wild type littermates, mice deficient in NMUR2 showed a reduced thermal nociceptive response in the hot plate, but not in the tail flick, test. In addition, the NMUR2 mutant mice showed a reduced behavioral response and a marked reduction in thermal hyperalgesia following capsaicin injection. NMUR2-deficient mice also showed an impaired pain response during the chronic, but not acute, phase of the formalin test. In contrast, NMUR1-deficient mice did not show any nociceptive differences compared to their wild type littermates in any of the behavioral tests used. We observed the same magnitude of inflammation in both lines of NMU receptor mutant mice compared to their wild type littermates after injection with complete Freund's adjuvant (CFA), suggesting no requirement for either receptor in this response. Thus, the pro-nociceptive effects of NMU in mice appear to be mediated through NMUR2, not NMUR1.

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    ABSTRACT: Neuromedin U (NMU) plays an important role in a number of physiological processes, but the relative contribution of its two known receptors, NMUR1 & NMUR2, is still poorly understood. Here we report the existence of a SNP T(1022)→A (Val(341)→Glu) in the third exon of the rat Nmur1 gene that leads to an inactive receptor. This SNP is present within the coding region of the highly conserved NPXXY motif found within all class A type G-protein coupled receptors (GPCRs), and translates to a NMUR1 receptor that is not expressed on the cell surface. Genetic analysis of the Nmur1 gene in a population of Sprague-Dawley rats revealed that this strain is highly heterogeneous for the inactivating polymorphism. The loss of functional NMUR1 receptors in Sprague-Dawley rats homozygous for the inactive allele was confirmed by radioligand binding studies on native tissue expressing NMUR1. The physiological relevance of this functional genomics finding was examined in two nociceptive response models. The pro-nociceptive effects of NMU were abolished in rats lacking functional NMUR1 receptors. The existence of naturally occurring NMUR1 deficient rats provides a novel and powerful tool to investigate the physiological role of NMU and its receptors. Furthermore, it highlights the importance of verifying the NMUR1 SNP status for rats used in physiological, pharmacological or toxicological studies conducted with NMUR1 modulators.
    Physiological Genomics 12/2012; 45(2). DOI:10.1152/physiolgenomics.00070.2012 · 2.81 Impact Factor
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    ABSTRACT: BACKGROUND: Previous studies have identified neuromedin U receptor 2 (NMUR2) as the subtype mediating the effects of neuromedin U on acute chemo-nociception induced by capsaicin or formalin injection. The aims of this study were to determine whether NMUR2 is required for the development of mechanical hypersensitivity after nerve injury or heat hypersensitivity after inflammation and whether there is a gender difference in the contribution of NMUR2 to nociception. METHODS: Mechanical sensitivity was assessed with von Frey filaments in wild type (WT) and NMUR2-null mice at baseline and following spared tibial nerve (STN) injury. Heat sensitivity was also assessed at baseline and after induction of inflammation with Freund's complete adjuvant (FCA). RESULTS: The response to von Frey filaments at baseline was similar for WT and NMUR2-null mice and for males and females. The response of male NMUR2-null mice was slightly but significantly decreased when exposed to 52 °C but not 58 °C heat stimuli. There was no difference between the stimulus-response curve for WT and NMUR2-null mice 7, 13 and 16 days after nerve injury. Similarly, after FCA-induced inflammation, there was no significant difference in heat hyperalgesia between WT and NMUR2-null mice or male or female mice in responses to temperatures ranging from 44 to 48 °C. CONCLUSIONS: The present data do not support a significant contribution of NMUR2 to the development of hypersensitivity after nerve injury or tissue inflammation, suggesting that pharmacological intervention aimed at the NMUR2 receptor might not be a valuable approach for the treatment of chronic pain.
    European journal of pain (London, England) 09/2013; 17(8). DOI:10.1002/j.1532-2149.2013.00288.x · 3.22 Impact Factor
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    Acta Pharmacologica Sinica 03/2012; 33(3):342-50. DOI:10.1038/aps.2011.200 · 2.50 Impact Factor

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