Primary afferent nociceptor mechanisms mediating NGF-induced mechanical hyperalgesia.
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 Cgamma (PLCgamma) all attenuate NGF-induced hyperalgesia. Although inhibitors of kinases downstream of PI3K and PLCgamma[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.
Malik-Hall
Misbah
M
NIH Pain Center (UCSF), Division of Neuroscience and Biomedical Sciences Program, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143, USA.
Dina
Olayinka A
OA
Levine
Jon D
JD
D000344:Afferent Pathways / Q000502:physiology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000139:chemically induced*; D016023:Integrins / Q000276:immunology; D008297:Male; D008954:Models, Biological; D009414:Nerve Growth Factors; D009619:Nociceptors / Q000502:physiology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D017288:Pain Threshold / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D016023:Integrins; D009414:Nerve Growth Factors; D020319:Oligodeoxyribonucleotides, Antisense; D020917:Receptor, trkA