Involvement of EphB1 Receptors Signalling in Models of Inflammatory and Neuropathic Pain

Abstract

EphB receptors tyrosine kinases and ephrinB ligands were first identified as guidance molecules involved in the establishment of topographical mapping and connectivity in the nervous system during development. Later in development and into adulthood their primary role would switch from guidance to activity-dependent modulation of synaptic efficacy. In sensory systems, they play a role in both the onset of inflammatory and neuropathic pain, and in the establishment of central sensitisation, an NMDA-mediated form of synaptic plasticity thought to underlie most forms of chronic pain. We studied wild type and EphB1 knockout mice in a range of inflammatory and neuropathic pain models to determine 1), whether EphB1 expression is necessary for the onset and/or maintenance of persistent pain, regardless of origin; 2), whether in these models cellular and molecular changes, e.g. phosphorylation of the NR2B subunit of the NMDA receptor, increased c-fos expression or microglial activation, associated with the onset of pain, are affected by the lack of functional EphB1 receptors. Differences in phenotype were examined behaviourally, anatomically, biochemically and electrophysiologically. Our results establish firstly, that functional EphB1 receptors are not essential for the development of normal nociception, thermal or mechanical sensitivity. Secondly, they demonstrate a widespread involvement of EphB1 receptors in chronic pain. NR2B phosphorylation, c-fos expression and microglial activation are all reduced in EphB1 knockout mice. This last finding is intriguing, since microglial activation is supposedly triggered directly by primary afferents, therefore it was not expected to be affected. Interestingly, in some models of long-term pain (days), mechanical and thermal hyperalgesia develop both in wild type and EphB1 knockout mice, but recovery is faster in the latter, indicating that in particular models these receptors are required for the maintenance, rather than the onset of, thermal and mechanical hypersensitivity. This potentially makes them an attractive target for analgesic strategies.

Ephrin‐B2 signaling in the spinal cord as a player in post‐inflammatory and stress‐induced visceral hypersensitivity

“…In rodents, upregulation of either the ligand, the receptor, or both, in DRGs and spinal cord, results in increased sensitivity to noxious stimuli and persistent pain. Upon peripheral nerve injury, 18,22,25,30 short-and long-term cutaneous inflammation, 15,18,29 or tumor cell implantation, 31,[50][51][52] increased gene or protein expression of the ephrins has been associated with thermal hyperalgesia or mechanical allodynia. Conversely, administration of ephrin-B2 small interfering RNAs significantly reduced mechanical allodynia in rats induced by spinal nerve crush.…”

“…Additionally, they showed that direct spinal application of ephrin-B2 activated EphB1/2 receptors and potentiated the pelvic urethra reflex further confirming that spinal ephrin-B2 signaling contributes to the development of visceral pain and/or hyperalgesia in the pelvic area. 33,64 Of interest, EphB1 knockout mice that underwent partial nerve ligation or exposed to mechanically or heat evoked pain significantly reduced their pain responses 17 and had accelerated recovery, 18 confirming that EphB1 is crucial in hypersensitivity in these murine models. Taken together, although more evidence about the exact mechanism is needed, our findings suggest ephrin-B2/EphB1 signaling as potential critical pathway that participates in the development and/or preservation of postinflammatory and stress-induced VHS.…”

Eph Receptors and Ephrins: Therapeutic Opportunities

“…The EphB/ephrin-B system has been implicated in the induction and persistence of various types of pain, including chronic neuropathic pain caused by peripheral nerve injury, inflammatory pain and cancer pain, as well as in the physical dependence to opiates (31; 34; 60). The mechanism underlying pain involves increased activation of postsynaptic EphB receptors (particularly EphB1) in neurons of the spinal cord by presynaptic ephrin-B ligands (particularly ephrin-B2) expressed in pain sensory neurons as well as hyperexcitability of the sensory neurons.…”

PKA is required for the modulation of spinal nociceptive information related to ephrinB–EphB signaling in mice

“…Recently, using EphB1 receptor homozygous knockout (EphB1À/À) mice, studies have provided evidence that the EphB1 receptor is required for the development of chronic pain and long-term potentiation (LTP) (Han et al, 2008;Liu et al, 2009;Cibert-Goton et al, 2013). However, the involvement of other members of the EphB receptor family has not yet been eliminated.…”