Urocortin 1 promotes trigeminal neuropathic pain by enhancing HSPB1-mediated interactions between neurons and non-neuronal cells in the trigeminal ganglion

Urocortins (UCNs), a family of peptides within the corticotropin-releasing factor (CRF) family, have been implicated in various functions, including stress, anxiety, and social behaviors. In this study, we demonstrate that UCN1 in the trigeminal ganglion (TG) plays a pivotal role in partial infraorbital nerve transection (pIONT)-induced TNP in mice. pIONT induced UCN1 upregulation in large-diameter TG neurons, and silencing Ucn1 using siRNA or adeno-associated virus (AAV)-mediated shRNA effectively attenuated pIONT-induced orofacial mechanical allodynia.

Furthermore, the transcription factor BTB-and-CNC homology 1 (BACH1) was identified as a direct regulator of Ucn1 expression, and knockdown of Bach1 reduced Ucn1 expression and alleviated pIONT-induced TNP. Mechanistically, pIONT increased the expression of corticotropin-releasing hormone receptor 1 (CRHR1), and intra-TG injection of UCN1 induced CRHR1-dependent mechanical allodynia, accompanied by activation of extracellular signal-regulated kinase (ERK) and cyclic-AMP responsive element binding protein (CREB), as well as upregulation of heat shock protein-1 (HSPB1).