HCN2 channels: a potential therapeutic target for orofacial neuropathic pain after trigeminal nerve injury

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have recently emerged as promising targets for the treatment of neuropathic pain. This study investigated the potential involvement of HCN2 channels in the development of trigeminal neuropathic pain following peripheral nerve injury. Infraorbital nerve chronic constriction injury (ION-CCI) model was adopted to rats, and head withdrawal thresholds (HWT) to mechanical stimulation were assessed pre- and postoperatively, as well as after pharmacological intervention. In the trigeminal ganglion (TG), intracellular cyclic adenosine monophosphate (cAMP) and cytoplasmic protein kinase A (PKA) levels were quantified by Enzyme-Linked Immunosorbent Assay (ELISA), while Hcn2 mRNA expression was evaluated by quantitative Polymerase Chain Reaction (qPCR). Immunohistochemical analysis was performed to assess phosphorylated cAMP response element-binding protein (pCREB) expression in the TG and HCN2 expression in infraorbital nerve (ION) axons. In the TG, cAMP and pCREB levels were elevated, whereas cytoplasmic PKA and Hcn2 mRNA levels were reduced. Axonal HCN2 expression was increased in CCI rats. On day 14, HWT was significantly reduced following CCI but was ameliorated by local administration of the HCN channel blocker ivabradine at the site of axonal injury. Collectively, these findings suggest that CCI-induced alterations in cAMP-PKA-pCREB signaling promote HCN2 accumulation in injured axons, thereby contributing to the development of orofacial neuropathic pain following peripheral nerve injury.