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. 2021 Jun 9:14:1643-1651.
doi: 10.2147/JPR.S311894. eCollection 2021.

ErbB4 in Spinal PV Interneurons Regulates Mechanical Allodynia in Neuropathic Pain via Modulation of Glycinergic Inhibitory Tone

Yingying Yu  1 , Guohua Wei  1 , Qi Zhou  1 , Huanhuan Sha  1
Affiliations

ErbB4 in Spinal PV Interneurons Regulates Mechanical Allodynia in Neuropathic Pain via Modulation of Glycinergic Inhibitory Tone

Yingying Yu et al. J Pain Res. .

Abstract

Background: Mechanical allodynia is the most common and challenging symptom associated with neuropathic pain; however, the underlying mechanisms are still unclear. The aim of this study was to investigate whether ErbB4, a receptor for neuregulin-1 (NRG1), participates in the modulation of mechanical allodynia.

Methods: Radiant heat and von Frey filaments were applied to assess nociceptive behaviors. Real-time quantitative polymerase chain reaction, Western blotting, immunofluorescence, and small interfering RNA were used to identify the likely mechanisms.

Results: ErbB4 was rapidly and persistently activated in spinal parvalbumin (PV) interneurons after chronic constriction injury (CCI) in mice. Knockdown of ErbB4 in the spinal cord prevented and reversed CCI-induced mechanical allodynia, and activation of ErbB4 by spinal application of NRG1 induced mechanical allodynia in naïve mice. Furthermore, we found that activation of ErbB4 decreased the glycine concentration in the spinal cord, contributing to modulation of mechanical allodynia.

Conclusion: ErbB4 in spinal PV interneurons gates mechanical allodynia in neuropathic pain via regulation of glycinergic inhibitory tone, suggesting that a possible ErbB4-mediated process participates in the development of neuropathic pain.

Keywords: Erb4; glycine; mechanical allodynia; parvalbumin interneuron.

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Conflict of interest statement

The authors declare no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Alterations in ErbB4 activation after CCI. (A and B), Mechanical allodynia (A) and heat hyperalgesia (B) was observed in the ipsilateral hindpaw after CCI, n=8. (C), Time course of ErbB4 and phosphor-ErbB4 (p-ErbB4) expression in the spinal cord after chronic constriction injury (CCI) or sham surgery, the representative Western blots were shown in left and the quantitative data was shown in right, n=6. (D), ErbB4 activation in the spinal cord on day 7 after (CCI, SNL), and SNI, n=6.
Figure 2
Figure 2
Cellular localization of p-ErbB4 expression in the spinal cord. (A and B), Combined p-ErbB4 and NeuN (a neural marker) (A) or parvalbumin (B) immunofluorescence staining in the spinal cord on day 7 after CCI or sham surgery. Scale bar, 25 μm.
Figure 3
Figure 3
Manipulation of ErbB4 in the spinal cord regulates pain behaviors. (A), The validation of ErbB4 siRNA transfection efficiency in vivo, n=4. (B and C), Effect of ErbB4 siRNA (10μg/5μL) on the development of CCI-induced mechanical allodynia (B) and thermal hyperalgesia (C), n=8. (D and E), Effect of ErbB4 siRNA (10μg/5μL) on the maintenance of CCI-induced mechanical allodynia (D) and thermal hyperalgesia (E), n=8. (F), Phosphorylation of ErbB4 after spinal administration of NRG1 (10μM/5μL), n=6. (G and H), Effect of NRG1 (10μM/5μL) on the mechanical allodynia (G) and thermal hyperalgesia (H) in naïve mice, n=8. (I and J), Effect of ErbB4 siRNA on the NRG1-induced mechanical allodynia (I) and thermal hyperalgesia (J) in naïve mice, n=8.
Figure 4
Figure 4
Inhibition of glycine release is required for the modulation of mechanical allodynia by ErbB4. (A and B), Effect of ErbB4 siRNA (10μg/5μL) on the release of spinal GABA and glycine in CCI mice, n=6. (C and D), Effect of NRG1 (10μM/5μL) on the release of spinal GABA and glycine in naive mice, n=6. (E), Bicuculline (0.05μg/5μL) and saclofen (5μg/5μL) have no effect on the decreased mechanical allodynia induced by ErbB4 siRNA in CCI mice, n=8. (F), Strychnine (1μg/5μL) reversed the decreased mechanical allodynia induced by ErbB4 siRNA in CCI mice, n=8. (G and H), Glycine (0.5μg/5μL), not muscimol (0.1μg/5μL) or baclofen (0.5μg/5μL), reversed the NRG1-induced mechanical allodynia in naïve mice, n=8. (I and J), Muscimol (0.1μg/5μL), baclofen (0.5μg/5μL), or Glycine (0.5μg/5μL) have no effect on the mechanical allodynia and thermal hyperalgesia induced by NRG1, n=8.
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