Abstract
Cortical neuroplasticity alterations are implicated in the pathophysiology of chronic orofacial pain. However, the relationship between critical cortex excitability and orofacial pain maintenance has not been fully elucidated. We recently demonstrated a top-down corticospinal descending pain modulation pathway from the anterior cingulate cortex (ACC) to the spinal dorsal horn that could directly regulate nociceptive transmission. Thus, we aimed to investigate possible corticotrigeminal connections that directly influence orofacial nociception in rats. Infraorbital nerve chronic constriction injury (IoN-CCI) induced significant orofacial nociceptive behaviors as well as pain-related negative emotions such as anxiety/depression in rats. By combining retrograde and anterograde tract tracing, we found powerful evidence that the trigeminal caudal subnucleus (Vc), especially the superficial laminae (I/II), received direct descending projections from granular and dysgranular parts of the insular cortex (IC). Extracellular signal-regulated kinase (ERK), an important signaling molecule involved in neuroplasticity, was significantly activated in the IC following IoN-CCI. Moreover, in IC slices from IoN-CCI rats, U0126, an inhibitor of ERK activation, decreased both the amplitude and the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and reduced the paired-pulse ratio (PPR) of Vc-projecting neurons. Additionally, U0126 also reduced the number of action potentials in the Vc-projecting neurons. Finally, intra-IC infusion of U0126 obviously decreased Fos expression in the Vc, accompanied by the alleviation of both nociceptive behavior and negative emotions. Thus, the corticotrigeminal descending pathway from the IC to the Vc could directly regulate orofacial pain, and ERK deactivation in the IC could effectively alleviate neuropathic pain as well as pain-related negative emotions in IoN-CCI rats, probably through this top–down pathway. These findings may help researchers and clinicians to better understand the underlying modulation mechanisms of orofacial neuropathic pain and indicate a novel mechanism of ERK inhibitor-induced analgesia.
Highlights
The orofacial region is often affected by chronic neuropathic pain conditions
We demonstrated that infraorbital nerve chronic constriction injury (IoN-CCI)-induced neuropathic pain led to the long-term activation of phosphorylated Extracellular signalregulated kinase (ERK) (p-ERK) in the insular cortex (IC)
Especially neuropathic pain, is always accompanied by increased negative emotions, including anxiety and/or depression (Zhuo, 2008). These negative emotions usually emerge in the late phase following nerve or tissue injury (Zhuo, 2008; Dai et al, 2011); we selected post-CCI-D14 to assess anxiety and/or depression by using the open field (OF) and elevated plus maze (EPM) tests
Summary
The orofacial region is often affected by chronic neuropathic pain conditions. Following orofacial surgical treatment such as third molar extraction, neuropathic pain, in addition to trigeminal neuralgia, sometimes occurs in the orofacial region and is difficult to diagnose and treat (Truelove, 2004; Zakharov et al, 2015). Orofacial nociceptive information is preliminarily transmitted to the trigeminal caudal subnucleus (Vc) in the brainstem and ascends to higher brain regions (Dubner and Bennett, 1983). Similar to that in the spinal cord, orofacial nociceptive transmission in the Vc of the brainstem receives descending inhibitory and facilitatory modulations from supraspinal structures such as the periaqueductal grey (PAG) and rostral ventromedial medulla (RVM) (Dubner and Bennett, 1983; Okubo et al, 2013; Wang et al, 2014; Feng et al, 2015). In addition to PAGRVM-Vc descending modulation pathways, a top-down pathway that originates from higher brain regions such as the cortex may directly regulate neurons of the Vc
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
