Nociceptor-expressed ephrin-B2 regulates inflammatory and neuropathic pain.
BACKGROUND
EphB receptors and their ephrin-B ligands play an important role in nervous system development, as well as synapse formation and plasticity in the adult brain. Recent studies show that intrathecal treatment with EphB-receptor activator ephrinB2-Fc induced thermal hyperalgesia and mechanical allodynia in rat, indicating that ephrin-B2 in small dorsal root ganglia (DRG) neurons and EphB receptors in the spinal cord modulate pain processing. To examine the role of ephrin-B2 in peripheral pain pathways, we deleted ephrin-B2 in Nav1.8+ nociceptive sensory neurons with the Cre-loxP system. Sensory neuron numbers and terminals were examined using neuronal makers. Pain behavior in acute, inflammatory and neuropathic pain models was assessed in the ephrin-B2 conditional knockout (CKO) mice. We also investigated the c-Fos expression and NMDA receptor NR2B phosphorylation in ephrin-B2 CKO mice and littermate controls.


RESULTS
The ephrin-B2 CKO mice were healthy with no sensory neuron loss. However, pain-related behavior was substantially altered. Although acute pain behavior and motor co-ordination were normal, inflammatory pain was attenuated in ephrin-B2 mutant mice. Complete Freund's adjuvant (CFA)-induced mechanical hyperalgesia was halved. Formalin-induced pain behavior was attenuated in the second phase, and this correlated with diminished tyrosine phosphorylation of N-methyl-D-aspartic acid (NMDA) receptor subunit NR2B in the dorsal horn. Thermal hyperalgesia and mechanical allodynia were significantly reduced in the Seltzer model of neuropathic pain.


CONCLUSIONS
Presynaptic ephrin-B2 expression thus plays an important role in regulating inflammatory pain through the regulation of synaptic plasticity in the dorsal horn and is also involved in the pathogenesis of some types of neuropathic pain.
Molecular Nociception Group, Wolfson Institute for Biomedical Research, Cruciform Building, University College London, London WC1E 6BT, UK.
Jing
J
Zhao
Guanglu
G
Yuan
Cruz M
CM
Cendan
Mohammed A
MA
Nassar
Malin C
MC
Lagerström
Klas
K
Kullander
Isabella
I
Gavazzi
John N
JN
Wood
D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000208:Acute Disease; D000818:Animals; D001522:Behavior, Animal; D002470:Cell Survival; D004195:Disease Models, Animal; D036388:Ephrin-B2 / Q000378:metabolism*; D005091:Exons / Q000235:genetics; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007249:Inflammation / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D019426:Integrases / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009437:Neuralgia / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D009475:Neurons, Afferent / Q000378:metabolism / Q000473:pathology; D009619:Nociceptors / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
D051700:Activating Transcription Factor 3; D036388:Ephrin-B2; D005904:Glial Fibrillary Acidic Protein; D062559:NAV1.8 Voltage-Gated Sodium Channel; C121001:NR2B NMDA receptor; D016760:Proto-Oncogene Proteins c-fos; D016194:Receptors, N-Methyl-D-Aspartate; C568318:Scn10a protein, mouse; C568319:Scn10a protein, rat; D015222:Sodium Channels; C045073:Cre recombinase; D019426:Integrases