Figure 5.
Working model of sexual dimorphism in a superficial dorsal horn mechanism underlying pathological pain. (A) In lamina I superficial dorsal horn (SDH) neurons, BDNF drives (1) disinhibition through KCC2 downregulation that (2) is coupled to reduced STEP61 activity and subsequent (3) phosphorylation and potentiation of GluN2B NMDARs by Fyn kinase. (B) We have found that this molecular mechanism of BDNF-mediated NMDAR potentiation is conserved across species in males, (C) but is not observed in the SDH of female rats and humans. (D) Rodent ovariectomy before reaching sexual maturity results in the male-like BDNF-induced hyperexcitability pathway, indicating that this sex difference is hormonally mediated. (E) We have found that the SDH STEP61/pFyn/pGluN2B spinal hyperexcitability pathway is not triggered by the in vivo CFA inflammatory pain or the ex vivo BDNF treatment models of pathological pain; however, it remains unknown if this molecular mechanism is involved in neuropathic pain models in females. (F) Further investigations are needed to identify the molecular mechanisms underlying spinal hyperexcitability and pathological pain in the female SDH. Figure created using BioRender.com.