Separation from a bonded partner alters neural response to inflammatory pain in monogamous rodents

Pain experience is known to be modified by social factors, but the brain mechanisms remain unspecified. We recently established an animal model of social stress-induced hyperalgesia (SSIH) using a socially monogamous rodent, the prairie vole, in which males separated from their female partners (loss males) became anxious and displayed exacerbated inflammatory pain behaviors compared to males with partners (paired males). In the present study, to explore the neural pathways involved in SSIH, a difference in neuronal activation in pain-related brain regions, or "pain matrix", during inflammatory pain between paired and loss males was detected using Fos immunoreactivity (Fos-ir). Males were paired with a female and pair bonding was confirmed in all subjects using a partner preference test. During formalin-induced inflammatory pain, both paired and loss males showed a significant induction of Fos-ir throughout the analyzed pain matrix components compared to basal condition (without injection), and no group differences in immunoreactivity were found among the injected males in many brain regions. However, the loss males had significantly lower Fos-ir following inflammatory pain in the medial prefrontal cortex and nucleus accumbens shell than the paired males, even though base Fos-ir levels were comparable between groups. Notably, both regions with different Fos-ir are major components of the dopamine and oxytocin systems, which play critical roles in both pair bonding and pain regulation. The present results suggest the possibility that pain exacerbation by social stress emerges through alteration of signaling in social brain circuitry.