Sex-specific spinal neurotrophin receptors mediate chronic stress-induced tactile allodynia in rats.

Here we investigated the effect of sex on the contribution of spinal BDNF-KCC2 pathway in chronic restraint stress-induced tactile allodynia. Chronic restraint stress induced tactile allodynia and elevated spinal BDNF levels in both sexes, with a greater increase in males. Intrathecal BDNF induced tactile allodynia in naïve female rats which was prevented by THX-B (a p75 neurotrophin receptor [p75NTR] antagonist), but not ANA-12 (a TrkB antagonist). In contrast, BDNF induced tactile allodynia in naïve male rats which was prevented by ANA-12, but not THX-B. Minocycline diminished allodynia and increased BDNF levels in both sexes, with a greater effect in stressed males. Intrathecal ANA-12 reversed allodynia in males, while THX-B reversed tactile allodynia in females with chronic stress. Conversely, 7,8-dihydroxyflavone induced tactile allodynia in naïve males but not females. Males exhibited greater Ntrk2 mRNA levels compared to females in naïve and stressed rats, whereas females showed greater Ngfr mRNA levels compared to males in stressed but not naïve rats. Intrathecal CLP257 (a KCC2 activator) partially reduced allodynia in both sexes. Interestingly, chronic stress increased KCC2 phosphorylation at threonine 1007 only in males. Orchidectomy abolished the antiallodynic effect of ANA-12 in males, while testosterone replacement restored it through the androgen receptor activation. Likewise, ovariectomy abolished the effect of THX-B in females, while estradiol replacement restored it through estrogen receptor-α activation. These findings suggest that chronic stress induces tactile allodynia through distinct molecular pathways: BDNF-TrkB signaling in males and BDNF-p75NTR signaling in females, with KCC2 dysfunction contributing to allodynia in both sexes.