There are striking similarities between neuropathic pain and opiate withdrawal-induced pain enhancement. Mechanisms of neuropathic pain and opiate dependence are complex and involve factors at the levels of receptors, ion channels, the cell and neural networks. Roles of diverse neurotransmitters, receptor systems and intracellular signaling proteins have been demonstrated in both neuropathic pain [
1‐
12] and opiate dependence [
13‐
24]. For instance, the system of glutamate/N-methyl-D-aspartate (NMDA) receptors/nitric oxide (NO) cascade is critically important to the development of neuropathic pain and morphine dependence and withdrawal [
11,
13,
14,
18,
19,
22‐
26]. However, the specific cellular and molecular mechanisms that control induction and maintenance of neuropathic pain and morphine dependence remain unclear. We have recently demonstrated a possibility that nerve injury or prolonged μ-opioid receptor (MOR) activation may elicit neuronal alterations that recapitulate events during development [
27‐
29]. Certain molecules and the molecule-mediated activities that are important during development and "silent" in matured nervous system may become activated after nerve injury or prolonged MOR activation and therefore involve in development of neuropathic pain and opiate dependence.
Receptor tyrosine kinases (RTKs) play vital roles in transmitting external signals to the inside of many types of cells. Eph RTKs and ephrins are involved in tissue-border formation, cell migration, axon guidance, synapse formation and neural circuit assembly during development of the nervous system [
30‐
33]. EphB receptors can also regulate development of glutamatergic synapses and their plasticity in adult nervous system by interaction with NMDA receptors [
34‐
36]. The NMDA receptors have an established role in neural plasticity and are fundamental mediators of expression, development and maintenance of neuropathic pain and opiate dependence [
21,
37‐
40]. Activation of the NMDA receptors results in Ca
2+ influx through the NMDA receptor ion-channel complex. The subsequent activation of various Ca
2+-dependent enzymes, such as Ca
2+/calmodulin-dependent kinase (CaMK) [
41‐
43] and extracellular signal-regulated kinase (ERK) [
44] play a critical role in induction of neuropathic pain and/or persistent opioid effects [
40]. EphB receptors continue to be expressed (at lower levels) in the adult nervous system and, after neural injury [
28,
29] or prolonged MOR activation [
27]. They are upregulated and redistributed in neurons, reactive astrocytes and oligodendrocytes [
27‐
29,
45‐
50]. Recent studies have shown that the EphB receptors can modulate sensory neuron excitability and spinal synaptic plasticity in acute inflammatory pain [
51], neuropathic pain [
9,
28,
29,
52] and opiate dependence [
27]. These studies demonstrate a critical role of the EphB receptors in the development of neuropathic pain and morphine dependence. Because of unavailability of the reagents and antibodies that could selectively activate and/or block a subtype of EphB receptor family, the specific EphB receptor that may play a key role in neuropathic pain and/or opiate dependence has not been identified. This study, using the EphB1 receptor homozygous knockout (
EphB1-/-) and heterozygous knockdown (
EphB1+/-) mice, provides the first evidence that the EphB1 receptor is required for development of neuropathic hyperalgesia and morphine dependence.