Fig. 11

Schematic diagrams of intrathecal 2R, 6R-HNK analgesia mechanism of in LF-PENS-induced CPP mouse model. A novel mouse model of CPP with comorbidities (anxiety, depression and/or cognitive impairment) is established by noninvasive LF‑PENS of popliteal fossa. Intrathecal 2R, 6R‑HNK produces potent analgesia on LF‑PENS‑induced CPP and alleviates the comorbidities depression and cognitive impairment in dose‑dependent manner. Mechanically, 2R, 6R‑HNK not only suppresses the upregulation of TRPA1 and other functional partners (including CGRP, TRPV1 and VGLUT2) in DRG neurons and neuronal excitability in the ascending pain pathways, but also decreases TRPA1‑ and TRPV1‑mediated Ca2+ influxes and CGRP overexpression in cultured DRG neurons. Together, TRPA1 is critical for the occurrence and development of CPP, as well as the potent analgesia of intrathecal 2R, 6R‑HNK