Phenotypic and neuroplastic changes in trigeminal nociceptive pathways following trigeminal nerve injury

Abstract: Trigeminal nerve injuries are often caused by dental and orofacial surgical procedures. Patients with trigeminal nerve injuries suffer from complex symptoms, such as persistent trigeminal neuropathic pain and affective distress, that interfere with daily activities. The underlying mechanisms linking somatic and affective symptoms remain to be clarified. We investigated the phenotypic and neuroplastic changes in trigeminal ganglion neurons and trigeminal spinal subnucleus caudalis (Vc) neurons in trigeminal neuropathic pain animal models that exhibited mechanical allodynia and heat hyperalgesia. In intact trigeminal ganglion, Aδ- and C-fiber afferents mainly transmit noxious information, while Aβ-fiber afferents transmit mechanosensitive tactile information. After the trigeminal nerves were injured, Aδ and C afferents became hyper-activated. Moreover, Aβ- afferents have been shown to upregulate calcitonin gene-related peptide (CGRP), a neuropeptide that is generally synthesized and released in nociceptive C afferents. Thus, in addition to Aδ and C afferents, Aβ afferents contribute to abnormal nociceptive signaling in the secondary neurons in the Vc after nerve injury. Vc neurons have projections that ascend to the ventral posteromedial thalamic nucleus (VPM) associated with sensory discrimination and parabrachial nuclei (PBN). After trigeminal nerve injury, C-fiber-mediated nociceptive inputs increased in Vc-VPM and Vc-PBN ascending pathways. However, Aβ-fiber-mediated mechanosensitive nociceptive inputs activated Vc neurons that specifically projected to the PBN. The PBN is a hub of multi-dimensional sensory processing, including visceral malaise, taste, temperature, itch, and affective aspects of pain, to the thalamus, hypothalamus, and extended amygdala. Therefore, our results suggest that phenotypic changes in Aβ afferents in the trigeminal ganglion and neuroplastic changes of Vc projecting to the PBN can underlie the development of pain and affective symptoms after trigeminal nerve injury. The PBN is a crucial structure for future investigations of the interaction between pain and affective problems, such as sleep disturbance and anorexia, in trigeminal nerve injury.