Given the above, our preclinical studies suggested that intrathecal 2R, 6R-HNK had an inhibitory efficacy in LF-PENS-induced comorbid depression and cognitive impairments, but not anxiety, which may be related to the inhibition of c-Fos, p-CREB and p-ERK expression in the involved brain regions. The gene discussed is CREB1; the disease is major depressive disorder.