Same pain, different brainstem: Sex-dependent astrocytic activation in the rostral ventromedial medulla during experimental osteoarthritis.

Abstract

OBJECTIVE: Osteoarthritis (OA) is the leading cause of chronic pain worldwide. Functional studies showed a critical role of descending facilitation, involving the rostral ventromedial medulla (RVM), in the establishment of pain chronicity. Glial cells such as microglia and astrocytes can contribute to chronic pain through the facilitation of neuronal excitability. This work aimed to characterize the morpho-structural changes in the RVM induced by experimental OA (eOA) pain and to identify potential sexual dimorphisms. METHODS: The kaolin/carrageenan model of eOA was induced in 23 male and 22 female Wistar Han rats. Four weeks later, brain samples were collected and divided into two analyses: stereological evaluation of changes in neuronal/glial cell density within the RVM, and immunohistochemical analysis of glial activation, astrocyte proliferation and structural changes. RESULTS: While no major differences were found in the RVM volume or area, osteoarthritic females exhibited a higher glia-to-neuron ratio (95%CI: 0.13-0.76; p=0.006), driven by increased glial cell density. A significant increase in GFAP-positive cells was observed in females (95%CI: 1.95-25.8; p=0.025), without a corresponding increase in Iba1 immunoreactivity, an effect not seen in males. Increased mitotic activity and structural complexity of astrocytes in osteoarthritic females were further confirmed by immunofluorescence and Sholl analysis, respectively. CONCLUSIONS: Our findings highlight the intricate relationship between eOA-related pain and the RVM cellular dynamics, revealing sex-specific astrocyte activation following eOA and its potential role in the mediation pain processing and chronification. These results suggest targeting astrocyte-mediated mechanisms as potential sex-specific therapeutic strategy for OA pain management.