Limits...
Nociceptor-expressed ephrin-B2 regulates inflammatory and neuropathic pain.

Zhao J, Yuan G, Cendan CM, Nassar MA, Lagerström MC, Kullander K, Gavazzi I, Wood JN - Mol Pain (2010)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, Cruciform Building, University College London, London WC1E 6BT, UK.

ABSTRACT

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.

Show MeSH

Related in: MedlinePlus

Both inflammatory and neuropathic pain behavior are attenuated in ephrin-B2  mutant mice. (A) Two phases (0 - 10 min, 10 - 60 min) of licking and biting behavior after intraplantar injection of formalin were analyzed, the second phase of which is attenuated in Efnb2 CKO mutant mice. (B) Intraplantar injection of carrageenan caused identical thermal hyperalgesia in Efnb2fl/fl controls and Efnb2 CKO mice. (C) Intraplantar injection of carrageenan caused a long-term mechanical allodynia in both Efnb2 CKO mutants and controls. (D) Intraplantar injection of CFA caused identical thermal hyperalgesia in Efnb2fl/fl controls and Efnb2 CKO mutant mice. (E) However, intraplantar injection of CFA caused a long-term mechanical allodynia that is attenuated after 4 hours in Efnb2 CKO mutants (two-way ANOVA, * p < 0.05). (F) Both Efnb2 CKO mutant mice and Efnb2fl/fl controls showed thermal hyperalgesia after sciatic nerve ligation (Seltzer model). However, thermal hyperalgesia was attenuated in Efnb2 CKO mutants (two-way ANOVA, * p < 0.05). (G) Sciatic nerve ligation following the Seltzer procedure caused a long-lasting mechanical allodynia that was attenuated after 5 days of surgery in Efnb2 CKO mutant mice (two-way ANOVA, * p < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2992507&req=5

Figure 4: Both inflammatory and neuropathic pain behavior are attenuated in ephrin-B2 mutant mice. (A) Two phases (0 - 10 min, 10 - 60 min) of licking and biting behavior after intraplantar injection of formalin were analyzed, the second phase of which is attenuated in Efnb2 CKO mutant mice. (B) Intraplantar injection of carrageenan caused identical thermal hyperalgesia in Efnb2fl/fl controls and Efnb2 CKO mice. (C) Intraplantar injection of carrageenan caused a long-term mechanical allodynia in both Efnb2 CKO mutants and controls. (D) Intraplantar injection of CFA caused identical thermal hyperalgesia in Efnb2fl/fl controls and Efnb2 CKO mutant mice. (E) However, intraplantar injection of CFA caused a long-term mechanical allodynia that is attenuated after 4 hours in Efnb2 CKO mutants (two-way ANOVA, * p < 0.05). (F) Both Efnb2 CKO mutant mice and Efnb2fl/fl controls showed thermal hyperalgesia after sciatic nerve ligation (Seltzer model). However, thermal hyperalgesia was attenuated in Efnb2 CKO mutants (two-way ANOVA, * p < 0.05). (G) Sciatic nerve ligation following the Seltzer procedure caused a long-lasting mechanical allodynia that was attenuated after 5 days of surgery in Efnb2 CKO mutant mice (two-way ANOVA, * p < 0.05).

Mentions: Tonic responses to intraplantar formalin were observed in formalin test [21]. The first phase (0-10 min) showed no significant difference in pain behavior between the two groups, but the second phase (10 - 60 min) was reduced in Efnb2 CKO mutant mice (t-test, p = 0.048). The mean numbers of lifting and biting of the injected paw was 390.3 ± 56.3 sec (Efnb2fl/fl, n = 8) and 248.6 ± 31.4 sec (Efnb2 CKO, n = 11) (Figure 4A). Interplantar injection with the inflammatory agent carrageenan leads to a pronounced thermal hyperalgesia and mechanical allodynia that were maintained over a period of 24 hours. However there were no significant difference showing between the ephrin-B2 CKO mice and floxed littermate controls (Figure 4B and 4C). We also tested inflammatory pain with CFA model. Thermal and mechanical responses were recorded at Day 1, 2, 5, 7, 9 and 14 after the CFA injection. Ten Efnb2 CKO mutant mice and ten Efnb2fl/fl controls were observed with Hargreaves and von Frey. Both groups had developed thermal hyperalgesia and mechanical allodynia 24 hours after CFA injection (Figure 4D and 4E). Both Efnb2 CKO mice and Efnb2fl/fl controls show the similar thermal hyperalgesia response (Figure 4D). However, the Efnb2 CKO mutants displayed overall less mechanical allodynia and significant differences were recorded from 5 days after injection (two-way ANOVA, p < 0.05) (Figure 4E).


Nociceptor-expressed ephrin-B2 regulates inflammatory and neuropathic pain.

Zhao J, Yuan G, Cendan CM, Nassar MA, Lagerström MC, Kullander K, Gavazzi I, Wood JN - Mol Pain (2010)

Both inflammatory and neuropathic pain behavior are attenuated in ephrin-B2  mutant mice. (A) Two phases (0 - 10 min, 10 - 60 min) of licking and biting behavior after intraplantar injection of formalin were analyzed, the second phase of which is attenuated in Efnb2 CKO mutant mice. (B) Intraplantar injection of carrageenan caused identical thermal hyperalgesia in Efnb2fl/fl controls and Efnb2 CKO mice. (C) Intraplantar injection of carrageenan caused a long-term mechanical allodynia in both Efnb2 CKO mutants and controls. (D) Intraplantar injection of CFA caused identical thermal hyperalgesia in Efnb2fl/fl controls and Efnb2 CKO mutant mice. (E) However, intraplantar injection of CFA caused a long-term mechanical allodynia that is attenuated after 4 hours in Efnb2 CKO mutants (two-way ANOVA, * p < 0.05). (F) Both Efnb2 CKO mutant mice and Efnb2fl/fl controls showed thermal hyperalgesia after sciatic nerve ligation (Seltzer model). However, thermal hyperalgesia was attenuated in Efnb2 CKO mutants (two-way ANOVA, * p < 0.05). (G) Sciatic nerve ligation following the Seltzer procedure caused a long-lasting mechanical allodynia that was attenuated after 5 days of surgery in Efnb2 CKO mutant mice (two-way ANOVA, * p < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992507&req=5

Figure 4: Both inflammatory and neuropathic pain behavior are attenuated in ephrin-B2 mutant mice. (A) Two phases (0 - 10 min, 10 - 60 min) of licking and biting behavior after intraplantar injection of formalin were analyzed, the second phase of which is attenuated in Efnb2 CKO mutant mice. (B) Intraplantar injection of carrageenan caused identical thermal hyperalgesia in Efnb2fl/fl controls and Efnb2 CKO mice. (C) Intraplantar injection of carrageenan caused a long-term mechanical allodynia in both Efnb2 CKO mutants and controls. (D) Intraplantar injection of CFA caused identical thermal hyperalgesia in Efnb2fl/fl controls and Efnb2 CKO mutant mice. (E) However, intraplantar injection of CFA caused a long-term mechanical allodynia that is attenuated after 4 hours in Efnb2 CKO mutants (two-way ANOVA, * p < 0.05). (F) Both Efnb2 CKO mutant mice and Efnb2fl/fl controls showed thermal hyperalgesia after sciatic nerve ligation (Seltzer model). However, thermal hyperalgesia was attenuated in Efnb2 CKO mutants (two-way ANOVA, * p < 0.05). (G) Sciatic nerve ligation following the Seltzer procedure caused a long-lasting mechanical allodynia that was attenuated after 5 days of surgery in Efnb2 CKO mutant mice (two-way ANOVA, * p < 0.05).
Mentions: Tonic responses to intraplantar formalin were observed in formalin test [21]. The first phase (0-10 min) showed no significant difference in pain behavior between the two groups, but the second phase (10 - 60 min) was reduced in Efnb2 CKO mutant mice (t-test, p = 0.048). The mean numbers of lifting and biting of the injected paw was 390.3 ± 56.3 sec (Efnb2fl/fl, n = 8) and 248.6 ± 31.4 sec (Efnb2 CKO, n = 11) (Figure 4A). Interplantar injection with the inflammatory agent carrageenan leads to a pronounced thermal hyperalgesia and mechanical allodynia that were maintained over a period of 24 hours. However there were no significant difference showing between the ephrin-B2 CKO mice and floxed littermate controls (Figure 4B and 4C). We also tested inflammatory pain with CFA model. Thermal and mechanical responses were recorded at Day 1, 2, 5, 7, 9 and 14 after the CFA injection. Ten Efnb2 CKO mutant mice and ten Efnb2fl/fl controls were observed with Hargreaves and von Frey. Both groups had developed thermal hyperalgesia and mechanical allodynia 24 hours after CFA injection (Figure 4D and 4E). Both Efnb2 CKO mice and Efnb2fl/fl controls show the similar thermal hyperalgesia response (Figure 4D). However, the Efnb2 CKO mutants displayed overall less mechanical allodynia and significant differences were recorded from 5 days after injection (two-way ANOVA, p < 0.05) (Figure 4E).

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, Cruciform Building, University College London, London WC1E 6BT, UK.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus