NRG1-ErbB4 signaling in the cerebrospinal fluid-contacting nucleus regulates thermal pain in mice

The cerebrospinal fluid-contacting nucleus(CSF-contacting nucleus) is a pair of unique nuclei in the brain parenchyma which has long been demonstrated to play an important role in pain signal processing. However, the mechanisms by which the CSF-contacting nucleus intervenes in pain is unclear. The NRG1-ErbB4 signaling plays an important role in the nervous system and has been shown to be involved in the regulation of pain. Whether there is an involvement of NRG1-ErbB4 signaling in the regulation of pain in the CSF-contacting nucleus is currently unknown. Here, our works showed that c-Fos expression in the CSF-contacting nucleus was increased in response to incisional pain. The activation of the CSF-contacting nucleus by chemogenetics could induce thermal hyperalgesia in naive mice without effecting the pain in mice suffering from incision pain. The inhibition of the CSF-contacting nucleus alleviated incision pain, but had no effect on the pain response in naive mice. With immunofluorescence staining and Western blot, the NRG1-ErbB4 signaling in the CSF-contacting nucleus showed upregulated during the acute pain phase. And, activating NRG1-ErbB4 signaling in the CSF-contacting nucleus specifically by intracranial injection of drugs, the naïve mice displayed thermal hyperalgesia while inhibiting this signaling by intracranial injection could reverse the hyperalgesia caused by CSF-contacting nucleus activation, and execute an analgesic effect during the painful phase in mice. Our study suggested that the CSF-contacting nucleus plays a regulatory role in thermal pain in mice via NRG1-ErbB4 signaling.