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

Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
Pain (Impact Factor: 5.64). 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: 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) 01/2013; · 3.37 Impact Factor
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    ABSTRACT: G protein-coupled receptors (GPCRs) play important roles in inflammation. Inflammatory cells such as polymorphonuclear leukocytes (PMN), monocytes and macrophages express a large number of GPCRs for classic chemoattractants and chemokines. These receptors are critical to the migration of phagocytes and their accumulation at sites of inflammation, where these cells can exacerbate inflammation but also contribute to its resolution. Besides chemoattractant GPCRs, protease activated receptors (PARs) such as PAR1 are involved in the regulation of vascular endothelial permeability. Prostaglandin receptors play different roles in inflammatory cell activation, and can mediate both proinflammatory and anti-inflammatory functions. Many GPCRs present in inflammatory cells also mediate transcription factor activation, resulting in the synthesis and secretion of inflammatory factors and, in some cases, molecules that suppress inflammation. An understanding of the signaling paradigms of GPCRs in inflammatory cells is likely to facilitate translational research and development of improved anti-inflammatory therapies.
    Acta Pharmacologica Sinica 03/2012; 33(3):342-50. · 2.35 Impact Factor
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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.
    Arthritis research & therapy 02/2012; 14(1):R29. · 4.27 Impact Factor

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