Journal
EUROPEAN JOURNAL OF NEUROSCIENCE
Volume 21, Issue 12, Pages 3387-3394Publisher
WILEY
DOI: 10.1111/j.1460-9568.2005.04173.x
Keywords
integrins; primary afferent nociceptor; rat; signalling pathways; TrkA
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The underlying mechanism for nerve growth factor (NGF) evoked pain and long-lasting mechanical hyperalgesia remains poorly understood. Using intrathecal antisense against the NGF receptor, receptor tyrosine kinase (TrkA), we found NGF to act at the primary afferent nociceptor directly in the Sprague-Dawley rat. Inhibitors of the three major pathways for TrkA receptor signalling, extracellular signal-related kinase (ERK)/mitogen-activated protein kinase kinase (MEK) (ERK/MEK), phosphatidylinositol 3-kinase (PI3K), and phospholipase C gamma (PLC gamma) all attenuate NGF-induced hyperalgesia. Although inhibitors of kinases downstream of PI3K and PLC gamma[glycogen synthetase kinase 3 (GSK3), calmodulin-dependent protein kinase II (CAMII-K) or protein kinase C (PKC)] do not reduce mechanical hyperalgesia, hyperalgesia induced by activation of PI3K was blocked by ERK/MEK inhibitors, suggesting cross-talk from the PI3K to the ERK/MEK signalling pathway. As integrins have been shown to modulate epinephrine and prostaglandin E-2-induced hyperalgesia, we also evaluated a role for integrins in NGF-induced mechanical hyperalgesia using beta(1)-integrin-specific antisense or antibodies.
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