Ovariectomy Exacerbates Chronic Constriction Injury-Induced Neuropathic Pain Through Dysregulation of Spinal Estrogen Receptor Balance in Rats

Estrogen depletion after menopause has been associated with altered pain sensitivity; however, the spinal mechanisms linking estrogen deficiency to neuropathic pain remain incompletely understood. This study investigated whether ovariectomy (OVX)-induced estrogen depletion exacerbates chronic constriction injury (CCI)-induced neuropathic pain and whether this effect is associated with changes in spinal estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) expression. Female Sprague Dawley rats underwent OVX or sham surgery, followed 5 weeks later by median nerve CCI or sham CCI. Mechanical withdrawal thresholds and thermal withdrawal latencies were evaluated using von Frey filaments and the plantar test, respectively. ERα and ERβ expression in the spinal dorsal horn was assessed via immunofluorescence staining and Western blotting. Selective ERα and ERβ agonists were administered intrathecally to examine their effects on OVX/CCI-induced pain behaviors. Plasma estradiol levels were significantly reduced after OVX, and OVX rats developed mechanical and thermal hypersensitivity. Rats in the OVX/CCI group exhibited more pronounced pain behaviors than those in the Sham/CCI group, indicating that OVX exacerbated CCI-induced neuropathic pain. In the spinal dorsal horn, ERα expression was increased in the OVX/Sham, Sham/CCI, and OVX/CCI groups, with the greatest increase observed in the OVX/CCI group. In contrast, ERβ expression was decreased in the Sham/CCI and OVX/CCI groups, with no significant difference between these groups. Intrathecal administration of an ERα agonist further aggravated mechanical allodynia and thermal hyperalgesia in OVX/CCI rats, whereas an ERβ agonist attenuated these pain behaviors. These findings suggest that OVX-induced estrogen depletion exacerbates CCI-induced neuropathic pain, potentially through a shift toward ERα-dominant signaling relative to ERβ in the spinal dorsal horn. Selective modulation of ERα and ERβ may therefore represent a potential therapeutic approach for chronic pain exacerbated by estrogen depletion.