Demyelination/remyelination and expression of interleukin-1β, substance P, nerve growth factor, and glial-derived neurotrophic factor during trigeminal neuropathic pain in rats

•Infraorbital nerve CCI model of trigeminal neuropathic pain in rats.•Axonal injury, glial cell proliferation, demyelination and partial remyelination.•Upregulation of IL-1β and SP and dysfunction of GDNF over time. The etiology of trigeminal neuropathic pain is not clear, but there is evidence that demyelination, expression of cytokines, neuropeptides, and neurotrophic factors are crucial contributors. In order to elucidate mechanisms underlying trigeminal neuropathic pain, we evaluated the time course of morphological changes in myelinated and unmyelinated trigeminal nerve fibers, expression of cytokine IL-1β, neuropeptide substance P (SP), nerve growth factor (NGF), and glial derived neurotrophic factor (GDNF) in peripheral and ganglion tissues, using a rat model of trigeminal neuropathic pain. Chronic constriction injury (CCI) of the infraorbital nerve (IoN), or a sham surgery, was performed. Mechanical allodynia was evaluated from day 3 to day 15 post-surgery. Trigeminal nerves were divided into 2 sections – distal to CCI and ganglion – for morphological analyses, immunohistochemistry (IL-1β, SP), and protein quantification by ELISA (NGF, GDNF). At early postoperative time points, decreased mechanical responses were observed, which were associated with demyelination, glial cell proliferation, increased immunoexpression of IL-1 β and SP, and impaired GDNF production. In the late postoperative period, mechanical allodynia was present with partial recovery of myelination, glial cell proliferation, and increased immunoreactivity of IL-1β and SP. Our data show that demyelination/remyelination processes are related to the development of pain behavior. IL-1β may have effects both in ganglia and nerves, while SP may be an important mediator at the nerve endings. Additionally, low levels of GDNF may produce impaired signaling, which may be involved in generation of pain.