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: 5.21). 09/2007; 130(3):267-78. DOI: 10.1016/j.pain.2007.01.036
Source: PubMed


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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Available from: Mark Sleeman
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    • "NMUR1 is widely expressed, and Nmur1-deficient mice have impaired contraction of certain smooth muscle tissues in the gastrointestinal tract [33]. NMUR2 is expressed primarily in the central nervous system, and Nmur2-deficient mice have been shown to have impaired responses to pain in some assays; in contrast, these pain responses were normal in Nmur1-deficient mice [20]. With respect to inflammatory responses, inflammation induced by the injection of complete Freund's adjuvant was normal in mice lacking both receptors [20]. "
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    ABSTRACT: Neuromedin U (NMU) is a neuropeptide with pro-inflammatory activity. The primary goal of this study was to determine if NMU promotes autoantibody-induced arthritis. Additional studies addressed the cellular source of NMU and sought to define the NMU receptor responsible for its pro-inflammatory effects. Serum containing arthritogenic autoantibodies from K/BxN mice was used to induce arthritis in mice genetically lacking NMU. Parallel experiments examined whether NMU deficiency impacted the early mast-cell-dependent vascular leak response induced by these autoantibodies. Bone-marrow chimeric mice were generated to determine whether pro-inflammatory NMU is derived from hematopoietic cells or stromal cells. Mice lacking the known NMU receptors singly and in combination were used to determine susceptibility to serum-transferred arthritis and in vitro cellular responses to NMU. NMU-deficient mice developed less severe arthritis than control mice. Vascular leak was not affected by NMU deficiency. NMU expression by bone-marrow-derived cells mediated the pro-arthritogenic effect. Deficiency of all of the known NMU receptors, however, had no impact on arthritis severity and did not affect the ability of NMU to stimulate intracellular calcium flux. NMU-deficient mice are protected from developing autoantibody-induced inflammatory arthritis. NMU derived from hematopoietic cells, not neurons, promotes the development of autoantibody-induced inflammatory arthritis. This effect is mediated by a receptor other than the currently known NMU receptors.
    Full-text · Article · Feb 2012 · Arthritis research & therapy
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    • "One that stands out is neuromedin U (NMU) which has been shown to have an emerging physiological role in nociception upon binding to the NMU receptor 2 [40]. Mice deficient in NMUR2 displayed reduced thermal nociceptive responses in the hot plate test, decreased thermal hyperalgesia following capsaicin injection and reduced the late phase response in the formalin test [41]. In other studies, NMU inhibited inflammation-mediated memory impairment and neuronal cell-death in rodents [42]. "
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    • "The effect of a high-fat diet on nociceptive behavioral responses was assessed via two acute thermal pain tests, the hotplate and tail-flick tests. These tests provided insight into nociceptive mechanisms generally believed to involve primarily supraspinal and spinal pathways, respectively [42]. The withdrawal latency for the hotplate test over the first 60 minutes of testing was significantly faster in LG mice and HG mice, compared with control mice (Figure 4a). "
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