Age and Sex Differences in Acute and Osteoarthritis-Like Pain Responses in Rats

Abstract

In this study, we investigated age and sex differences in acute and chronic pain in rats. Groups of young (3–6 months) and aged (20–24 months) male and female Fischer 344 rats were used to assess basal thermal and mechanical thresholds, capsaicin-induced acute nocifensive responses and c-Fos expression in the spinal cord, and monoiodoacetate (MIA)-induced knee osteoarthritis (OA)-like pain responses. There was a significant sex, but not age, effect on thermal threshold on the hindpaw and mechanical threshold on the knee joint. No significant age and sex differences in capsaicin-induced nocifensive and c-Fos responses were observed. MIA induced a greater peak reduction of weight-bearing responses in aged males than young rats. Aged females developed the most profound weight-bearing deficit. With knee joint sensitivity as a primary outcome measure, MIA induced more pronounced and longer-lasting hyperalgesia in older rats, with aged female rats showing the worst effect. These data suggest that age may not have significant effect on acute nociceptive processing, but it significantly impacts OA-like pain, making aged rats, especially females, more vulnerable to chronic pain conditions. These preclinical models should provide important tools to investigate basic mechanisms underlying the impact of age and sex in chronic pain conditions.

Pain modulatory network is influenced by sex and age in a healthy state and during osteoarthritis progression in rats

“…OF rats had increased PAG FC with thalamus, retrosplenial cortex, and entorhinal cortex relative to YM, YF, and OM rats (Figure 2d). Group differences in PAG FC with the whole brain were statistically modest in the early phase, possibly due to the high pain behavior observed in all groups at this time point (Ro et al, 2020). However, YF had increased PAG FC with several brain regions compared to other groups, such as basal ganglia, NAc, cACC, and motor and somatosensory cortical areas.…”

“…OF rats had increased PAG FC with caudate putamen, NAc, insula, primary and secondary somatosensory cortices, parabrachial pigmented nucleus of the ventral tegmental area, raphe nuclei, retrosplenial cortex, entorhinal cortex, and cerebellum relative to YM, YF, and OM rats (Figure 3d). Notably, YM showed enhanced PAG FC with rACC, which may demonstrate a strong endogenous inhibitory capacity and a potential mechanism underlying the full recovery from OA‐induced hyperalgesia at this time point (Da Silva et al, 2020; Ro et al, 2020). Females, regardless of age, showed increased PAG FC with raphe nuclei (see also Figure ).…”

“…PAG FC is modulated by sex and age at baseline, and OA pain alters PAG FC and activity in humans and animals (Abaei et al, 2016; Chen et al, 2015). Furthermore, the progression of OA pain behavior over time is also modulated by sex and age in rats (Ro et al, 2020). Thus, we first decided to investigate the impact of sex and age on OA‐induced alterations in PAG FC during the early phase of MIA‐induced OA.…”

“…The early phase (0–10 days) is associated with hypersensitivity mostly driven by the initial inflammatory phase, whereas the late phase (14–28 days) is associated with established pain behaviors and the progression of subchondral bone lesions that mimic those observed in OA patients (Bove et al, 2003; Mapp et al, 2013). Using the MIA‐induced OA model in Fisher rats, we reported that hyperalgesia lasts longer and is more pronounced in older rats, with aged female rats showing the most impaired responses (Ro et al, 2020). This data are consistent with human studies and suggest that age significantly impacts OA‐like pain, making the elderly, particularly females, more vulnerable to chronic OA pain (Felson et al, 1987; Shane Anderson & Loeser, 2010).…”

The search for translational pain outcomes to refine analgesic development: Where did we come from and where are we going?

“…There is good overall agreement between the results with both types of assay, such that when sex differences are found with the standard methods, they are also often reported in alternative pain surrogates (e.g. Kohli et al, 2010;Burke et al, 2013;Ro et al, 2019). However, there are also reported discrepancies between attempts to detect sex differences in both standard pain outcomes and novel pain surrogates (Perissin et al, 2003;Freeman et al, 2008;Kandasamy et al, 2016;) (see Supplementary Table 2).…”