Clinical pain can be caused by tissue injury (inflammatory pain) and by nerve injury (neuropathic pain) and is typically characterized by hyperalgesia (increased responsiveness to noxious stimuli) and allodynia (painful responses to innocuous stimuli). Changes in the peripheral terminals of primary sensory neurons may lead to peripheral sensitization (an increased transduction sensitivity of nociceptors) whilst changes in the excitability of spinal dorsal horn neurons can result in central sensitization (an increased gain of sensory transmission), two major mechanisms contributing to pain hypersensitivity. Although short-term pain hypersensitivity is transcription-independent, persistent pain hypersensitivity may be the result of gene transcription- and protein synthesis-dependent mechanisms.
The aim of this proposal is to assess the involvement of the MAPK (mitogen-activated protein kinase) family member ERK (extracellular signal-regulated protein kinase) in mediating both post-translational and transcriptional changes which contribute to inflammatory and neuropathic pain hypersensitivity. The project will examine ERK activation in primary sensory neurons in the dorsal root ganglia (DRG) and in dorsal horn neurons in vivo and in vitro and will test the hypotheses that 1) ERK activation contributes to peripheral and central sensitization, 2) ERK activation leads to CREB phosphorylation and the expression of CRE-containing genes in DRG and dorsal horn neurons, and 3) ERK activation contributes to the induction and maintenance of inflammatory pain and neuropathic pain. A number of different approaches, including immunostaining, western blot, and in situ hybridization to detect protein and mRNA expression, will be used, as well as behavioral tests. These results should provide insights into the role of intracellular signal transduction cascades in the pathogenesis of pain.
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