Two new studies shed light on the functions of the Eph receptor tyrosine kinases and their ephrin ligands in the spinal cord. The data highlight roles in pain processing and the control of locomotion, an understanding of which might contribute to the development of therapies for chronic pain and spinal cord injury.

Recently, interactions between EphB and NMDA (N-methyl-D-aspartate) receptors were shown to regulate synaptic plasticity at glutamatergic synapses in the hippocampus. As NMDA receptors are also key mediators of plasticity in pain-processing regions of the spinal cord, Battaglia and colleagues wondered whether EphB receptors might have a regulatory role in nociceptive pathways.

Activation of postsynaptic EphB receptors on dorsal horn neurons by intrathecal injection of ephrinB2 coupled to an Fc antibody fragment induced thermal hyperalgesia in adult wild-type rats. Pretreatment with an NMDA receptor antagonist prevented the development of hyperalgesia in ephrinB2–Fc-injected rats, indicating that EphB receptors modulate synaptic transmission through NMDA receptors. Co-precipitation of increased amounts of phosphorylated Src with EphB receptors in ephrinB2–Fc-treated rats implied a role for the Src kinase family in the signalling pathway between EphB and NMDA receptors.

Interactions between NMDA and Eph receptors might also contribute to the control of locomotion, according to a report by Kullander et al. in Science. Addition of serotonin and NMDA to isolated spinal cords of newborn mice produced rhythmic, left-to-right alternating activity in the lumbar segments that control limb movement. By contrast, outputs from the cords of mutant mice lacking either the EphA4 receptor or ephrinB3 did not alternate rhythmically, but tended towards an abnormal synchronous pattern that results in the rabbit-like gait of these mutants. EphA4-null mice exhibited aberrant projection of fibres across the midline of the cord, indicating that correct wiring of the neuronal networks that control locomotion relies on recognition of ephrinB3 in the midline by EphA4 receptors.