TrkB signaling is required for both the induction and maintenance of tissue and nerve injury-induced persistent pain.
Activation of primary afferent nociceptors produces acute, short-lived pain, and tissue or nerve injury induces long-term enhancement of nociceptive processing, manifested as hypersensitivity to thermal and mechanical stimulation. Here we used a chemical-genetic and pharmacological approach to study the contribution of the receptor tyrosine kinase, type 2 (TrkB) to the generation and maintenance of injury-induced persistent pain. We performed the studies in wild-type mice and transgenic (TrkB(F616A)) mice that express mutant but fully functional TrkB receptors. By injecting a small molecule derivative of the protein kinase inhibitor protein phosphatase 1 (1NM-PP1), it is possible to produce highly selective inhibition of TrkB autophosphorylation in adult mice, without interfering with the activity of other protein kinases. We report that oral administration of 1NM-PP1, at doses that blocked phosphorylation of TrkB in the spinal cord, had no effect in behavioral tests of acute heat, mechanical, or chemical pain sensitivity. However, the same pretreatment with 1NM-PP1 prevented the development of tissue- or nerve injury-induced heat and mechanical hypersensitivity. Established hypersensitivity was transiently reversed by intraperitoneal injection of 1NM-PP1. Although interfering with TrkB signaling altered neither acute capsaicin nor formalin-induced pain behavior, the prolonged mechanical hypersensitivity produced by these chemical injuries was prevented by 1NM-PP1 inhibition of TrkB signaling. We conclude that TrkB signaling is not only an important contributor to the induction of heat and mechanical hypersensitivity produced by tissue or nerve injury but also to the persistence of the pain.
Wang
Xidao
X
Department of Anatomy and W. M. Keck Foundation Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, California 94158, USA.
Ratnam
Joseline
J
Zou
Bende
B
England
Pamela M
PM
Basbaum
Allan I
AI
D000818:Animals; D002908:Chronic Disease; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009437:Neuralgia / Q000235:genetics / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013268:Stimulation, Chemical
C479693:1-tert-butyl-3-naphthalen-1-ylmethyl-1H-pyrazolo(3,4-d)pyrimidin-4-ylemine; D011720:Pyrazoles; D011743:Pyrimidines; D020813:Receptor, trkB