Nociceptor-derived brain-derived neurotrophic factor regulates acute and inflammatory but not neuropathic pain.
Conditional mouse knock-outs provide an informative approach to drug target validation where no pharmacological blockers exist or global knock-outs are lethal. Here, we used the Cre-loxP system to delete BDNF in most nociceptive sensory neurons. Conditional null animals were healthy with no sensory neuron loss. However, pain-related behavior was substantially altered. Baseline thermal thresholds were reduced. Carrageenan-induced thermal hyperalgesia was inhibited. Formalin-induced pain behavior was attenuated in the second phase, and this correlated with abolition of NMDA receptor NR1 Ser896/897 phosphorylation and ERK1 and ERK2 activation in the dorsal horn; AMPA receptor phosphorylation (GluR1/Ser831) was unaffected. NGF-induced thermal hyperalgesia was halved, and mechanical secondary hyperalgesia caused by intramuscular NGF was abolished. By contrast, neuropathic pain behavior developed normally. Nociceptor-derived BDNF thus plays an important role in regulating inflammatory pain thresholds and secondary hyperalgesia, but BDNF released only from nociceptors plays no role in the development of neuropathic pain.
Zhao
Jing
J
Molecular Nociception Group, Department of Biology, University College London, London WC1E 6BT, UK.
Seereeram
Anjan
A
Nassar
Mohammed A
MA
Levato
Alessandra
A
Pezet
Sophie
S
Hathaway
Gareth
G
Morenilla-Palao
Cruz
C
Stirling
Caroline
C
Fitzgerald
Maria
M
McMahon
Stephen B
SB
Rios
Maribel
M
Wood
John N
JN
D000208:Acute Disease; D000344:Afferent Pathways / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism / Q000503:physiopathology; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009437:Neuralgia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009475:Neurons, Afferent / Q000378:metabolism; D009619:Nociceptors / Q000378:metabolism*; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D010766:Phosphorylation; D020671:Posterior Horn Cells / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D018836:Inflammation Mediators; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D048052:Mitogen-Activated Protein Kinase 3