1. In the companion paper, we described a state of hypersensitivity that developed in dorsal horn wide dynamic range (WDR) neurons in rats after transient spinal cord ischemia. Thus the WDR neurons exhibited lower threshold and increased responses to low-intensity mechanical stimuli. The response pattern of these neurons to suprathreshold electrical stimulation was also changed. Notably, the response to A-fiber input was increased. No change in response to thermal stimulation was found before and after spinal cord ischemia. 2. In normal rats, the gamma-aminobutyric acid (GABA)B agonist baclofen (0.1 mg/kg ip) administered 1-3 h before neuronal recording suppressed the responses of WDR neurons to high-intensity mechanical pressure without influencing the threshold and the responses to lower-intensity stimuli. 3. In allodynic rats, similar pretreatment with baclofen totally reversed the hypersensitivity of the WDR neurons to mechanical stimuli and normalized the response pattern of neurons to electrical stimulation. 4. The GABAA receptor agonist muscimol (1 mg/kg ip) did not influence the response of WDR neurons in either normal or allodynic animals. 5. The present results demonstrated that the GABAB agonist baclofen is effective in reversing the hypersensitivity of dorsal horn WDR neurons to low-intensity mechanical stimulation after transient spinal cord ischemia, indicating that dysfunction of the GABAergic inhibitory system may be responsible for the development of neuronal hypersensitivity. 6. It is suggested that GABAergic interneurons exert a tonic presynaptic inhibitory control, through baclofen-sensitive B-type GABA receptors, on input from low-threshold mechanical afferents, and that disruption of this control may result in painful reaction to innocuous stimuli (allodynia).

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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.