Elucidation of Molecular Mechanisms of Pain : Role of PKC and NGF on spinal sensitization in the pathological state following peripheral tissue injury

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The somatosensory system of spinal cord are directly involved into the modulation of peripheral nociceptive input with acute and/or chronic peripheral C-fibers activation following tissue injury. However, under certain condition, there is a pathological state which is functionally characterized by an increased response to noxious stimuli (hyperalgesia), and the reduction of pain threshold (allodynia). The aim of the present study was to examine the molecullar mechanism of the observed pathological pain state may reflect an abnormal intracellular signaling resulting in increased intracellular Ca ion caused by excessive release of glutamate and substance P and increased syntheses of a variety of growth factors (NGF) using well-established rat model.The followings are possible mechanisms based on the present study.1.Pain and neuronal plasticity following peripheral tissue inflammationIncreased peripheral C-fiber activity resulting from formalin or mustard oil hind paw injection evokes 1) … More excessive release of spinal glutamate (by microdialysis), 2) NMDA antagonist blocked hyperalgesia-> increased neuronal activity of dorsal horn resulting from activation of NMDA receptor and corresponding massive increase in intracellular Ca^<++>,3) Staurosporine (PKC inhivitor) supressed glutamate release and hyperalgesia -> activation of PLA2, PLC which evokes synthesis of arachidonic acid (PGs) and protein kinase C (PKC), these substances and enzyme iniciate positive feed back in spinal cord (sustained facilitation), 4) "up-regulation" of synaptic transmission within the spinal cord functionally expressed as 5) increased responsivity of spinal cord neurons to peripheral stimulus i.c. "central sensitization" : allodynia and/or hyperalgesia.2.Involvement of nerve growth factor (NGF) in facilitated pain state.The biological role of NGF in the developing and restoring processes after peripheral nerve injury has been most intensively studied. There is evidence suggesting its role as a target-derived neurotrophic factor, regulating the density of innervation in a variety of peripheral tissues. The role of NGF in the adult animal is less well characterized, but there is increasing evidence including present results to suggest that NGF is a peripheral mediator in facilitated inflammatory pain states. 1) the high affinity NGF receptor is expressed with sP in C-fiber (trkA),2) 4-methyl cathechol (4MC), which increases NGF,caused enhancement of hyperalgesia in a dosc deppendent manner produced by injecting mustard oil. -> NGF treatment can facilitate glutamate and sP mediated synaptic transmission, and can lead to central sensitization. 3) NGF immunoreactivity of spinal cord was increased to compensate dendritic damage of neuron (decreased MAP-2 immunoreactivity) after formalin injection -> this may be caused by interacting with interleukin-1 (IL-1) * activated macrophage where the IL-1 is the key mediator on NGF-mRNA levels.Taken together, these evidences strongly suggest that NGF is necessary for the maintenance of the up-regulation can lead to a peripheral and central sensitization. In the future study, we need to elucidate further such as the theories proposed to explain how the peripheral injury or noxicious stimulation lead to the alteration in neuronal plasticity and how to play a role of NGF in facilitating state and neuronal degeneration in chronic state. Less