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Impaired inflammatory pain and thermal hyperalgesia in mice expressing neuron-specific dominant negative mitogen activated protein kinase kinase (MEK)

DOI: 10.1186/1744-8069-2-2

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Formalin-induced second phase spontaneous pain behaviors as well as thermal hyperalgesia measured 1 – 3 hours post-formalin were significantly reduced in the DN MEK mice when compared to their wild type littermate controls. In addition, spinal ERK phosphorylation following formalin injection was significantly reduced in the DN MEK mice. This was not due to a reduction of the number of unmyelinated fibers in the periphery, since these were almost double the number observed in wild type controls. Further examination of the effects of suppression of MEK function on a downstream target of ERK phosphorylation, the A-type potassium channel, showed that the ERK-dependent modulation of the A-type currents is significantly reduced in neurons from DN MEK mice compared to littermate wild type controls.Our results demonstrate that the neuronal MEK-ERK pathway is indeed an important intracellular cascade that is associated with formalin-induced inflammatory pain and thermal hyperalgesia.Extracellular signal-regulated kinases (ERKs) belong to a cascade that is part of a phosphorelay system composed of three sequentially activated kinases regulated by phosphorylation. Initiation of this cascade occurs via multiple mechanisms which ultimately activate raf kinases. Activated raf phosphorylates MEK which phosphorylates ERK1 and ERK2 on tyrosine and threonine residues. Extracellular signal-regulated kinases are involved in the regulation of meiosis and mitosis, and in differentiated cells, ERKs integrate a wide variety of postmitotic functions [1-3]. Within the past decade, numerous studies in rodents have elucidated the role of ERKs in nociceptive plasticity. ERK activation is activity-dependent, and occurs following noxious stimulation [4,5]. The role of ERK in nociceptive plasticity has been extensively studied in the spinal cord and dorsal root ganglia, two important sites of nociceptive sensitization [6-9]. In addition to different types of noxious stimuli, high intensity electri


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