Nociceptor-derived brain-derived neurotrophic factor regulates acute and inflammatory but not neuropathic pain

• Published in: Molecular and cellular neuroscience 2006-03, Vol.31 (3), p.539-548
• Main Authors: Zhao, Jing, Seereeram, Anjan, Nassar, Mohammed A., Levato, Alessandra, Pezet, Sophie, Hathaway, Gareth, Morenilla-Palao, Cruz, Stirling, Caroline, Fitzgerald, Maria, McMahon, Stephen B., Rios, Maribel, Wood, John N.
• Format: Article
• Language: English
• Subjects: Acute Disease; Afferent Pathways - metabolism; Afferent Pathways - physiopathology; Animals; BDNF; Brain-Derived Neurotrophic Factor - genetics; Brain-Derived Neurotrophic Factor - physiology; Cells, Cultured; Conditional knock-outs; Disease Models, Animal; DRG; ERK1; ERK2; Female; Ganglia, Spinal - metabolism; Ganglia, Spinal - physiopathology; Hyperalgesia - genetics; Hyperalgesia - metabolism; Hyperalgesia - physiopathology; Inflammation - genetics; Inflammation - metabolism; Inflammation - physiopathology; Inflammation Mediators - pharmacology; Inflammatory pain; Life Sciences; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 3 - metabolism; Neuralgia - genetics; Neuralgia - metabolism; Neuralgia - physiopathology; Neurons and Cognition; Neurons, Afferent - metabolism; Neuropathic pain; NMDA receptor; Nociceptors - metabolism; Pain Measurement; Pain Threshold - physiology; Peripheral Nervous System Diseases - genetics; Peripheral Nervous System Diseases - metabolism; Peripheral Nervous System Diseases - physiopathology; Phosphorylation; Posterior Horn Cells - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2005.11.008

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 Ser 896/897 phosphorylation and ERK1 and ERK2 activation in the dorsal horn; AMPA receptor phosphorylation (GluR1/Ser 831) 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.