Old age and female sex are risk factors for the development of osteoarthritis (OA)
and chronic pain. We investigated the effects of sex and age on pain modulatory networks
in a healthy state and during OA progression. We used functional MRI to determine
the effects of sex and age on periaqueductal gray functional connectivity (PAG FC)
in a healthy state (pre-OA) and during the early and late phases of monosodium iodoacetate
(MIA)-induced OA in male and female Fischer 344 rats (young, 3-6 mo / old, 20-24 mo).
For functional MRI, rats were scanned using a Bruker 7T MRI (TR = 1500 ms, in plane
resolution = 400 μm, slice thickness 1 mm, acquisition time: 15 minutes) and under
isoflurane anesthesia ≤ 1.5%. We then examined how sex and age affect longitudinal
changes in PAG FC in OA. In a healthy state, females exhibited more widespread PAG
FC than males, and this effect was exaggerated with aging. Young males had moderate
PAG FC changes during the early phase but recruited additional brain regions, including
the rostral anterior cingulate cortex (ACC), during the late phase. Young females
exhibited widespread PAG FC in the early phase, which includes connections to insula,
caudal ACC, and nucleus accumbens (NAc). Older groups had strong PAG FC with fewer
regions in the early phase, but they recruited additional brain regions, including
NAc, in the late phase. Overall, our findings show that PAG FC is modulated by sex
and age in a healthy state. A widespread PAG network in the early phase of OA pain
may contribute to the transition from acute to chronic OA pain and the increased risk
of developing chronic pain for females. Enhanced PAG FC with the reward system may
represent a potential mechanism underlying chronic OA pain in elderly patients. NIH-NIA
grant AG053783 (JYR) and NIH-NIDCR grant DE0027808 (JYR).
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