Hui‐Lin Pan

Hypertension is a major adverse effect of calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporine, used clinically as immunosuppressants. Calcineurin inhibitor‐induced hypertension (CIH) is linked to augmented sympathetic output from the hypothalamic paraventricular nucleus (PVN). GluA2‐lacking, Ca 2+ ‐permeable AMPA receptors (CP‐AMPARs) are a key feature of glutamatergic synaptic plasticity, yet their role in CIH remains elusive. Here, we found that systemic administration of FK506 in rats significantly increased serine phosphorylation of GluA1 and GluA2 in PVN synaptosomes. Strikingly, FK506 treatment reduced GluA1/GluA2 heteromers in both synaptosomes and endoplasmic reticulum‐enriched fractions from the PVN. Blocking CP‐AMPARs with IEM‐1460 induced a larger reduction of AMPAR‐mediated excitatory postsynaptic current (AMPAR‐EPSC) amplitudes in retrogradely labelled, spinally projecting PVN neurons in FK506‐treated rats than in vehicle‐treated rats. Furthermore, FK506 treatment shifted the current–voltage relationship of AMPAR‐EPSCs from linear to inward rectification in labelled PVN neurons. FK506 treatment profoundly enhanced physical interactions of α2δ‐1 with GluA1 and GluA2 in the PVN. Inhibiting α2δ‐1 with gabapentin, α2δ‐1 genetic knockout, or disrupting α2δ‐1–AMPAR interactions with an α2δ‐1 C terminus peptide restored GluA1/GluA2 heteromers in the PVN and diminished inward rectification of AMPAR‐EPSCs in labelled PVN neurons induced by FK506 treatment. Additionally, microinjection of IEM‐1460 or α2δ‐1 C terminus peptide into the PVN reduced renal sympathetic nerve discharges and arterial blood pressure elevated in FK506‐treated rats but not in vehicle‐treated rats. Thus, calcineurin in the hypothalamus constitutively regulates AMPAR subunit composition and phenotypes by controlling GluA1/GluA2 interactions with α2δ‐1. Synaptic CP‐AMPARs in PVN presympathetic neurons contribute to augmented sympathetic outflow in CIH. image Key points Systemic treatment with the calcineurin inhibitor increases serine phosphorylation of synaptic GluA1 and GluA2 in the PVN. Calcineurin inhibition enhances the prevalence of postsynaptic Ca 2+ ‐permeable AMPARs in PVN presympathetic neurons. Calcineurin inhibition potentiates α2δ‐1 interactions with GluA1 and GluA2, disrupting intracellular assembly of GluA1/GluA2 heterotetramers in the PVN. Blocking Ca 2+ ‐permeable AMPARs or α2δ‐1–AMPAR interactions in the PVN attenuates sympathetic outflow augmented by the calcineurin inhibitor.

Oral cancer pain remains a significant public health concern. Despite the development of improved treatments, pain continues to be a debilitating clinical feature of the disease, leading to reduced oral mobility and diminished quality of life. Opioids are the gold standard treatment for moderate-to-severe oral cancer pain; however, chronic opioid administration leads to hyperalgesia, tolerance, and dependence. The aim of this review is to present accumulating evidence that epidermal growth factor receptor (EGFR) signaling, often dysregulated in cancer, is also an emerging signaling pathway critically involved in pain and opioid tolerance. We presented preclinical and clinical data to demonstrate how repurposing EGFR inhibitors typically used for cancer treatment could be an effective pharmacological strategy to treat oral cancer pain and to prevent or delay the development of opioid tolerance. We also propose that EGFR interaction with the µ-opioid receptor and glutamate N-methyl-D-aspartate receptor could be two novel downstream mechanisms contributing to pain and morphine tolerance. Most data presented here support that repurposing EGFR inhibitors as non-opioid analgesics in oral cancer pain is promising and warrants further research.