Valproate inhibits orofacial and somatic hyperalgesia induced by maternal separation through decreasing IL-6 expression in the medial prefrontal cortex and spinal cord in rats.

Sodium valproate (VPA), a histone deacetylase (HDAC) inhibitor, has been shown to have analgesic effects and may be involved in analgesia through anti-inflammatory mechanisms. However, little is known about the involvement of VPA in the treatment of comorbid chronic pain conditions such as fibromyalgia syndrome (FMS) and temporomandibular disorder (TMD). In the present study, we used maternal separation (MS) stress model to simulate childhood stress-induced orofacial and somatic hyperalgesia at different age stages to mimic the overlapping pain symptoms of patients with TMD and FMS comorbidity. We found that MS stress induced consistent orofacial and somatic hyperalgesia in both male and female adolescent and adult rats, but there were no differences in the hyperalgesia between male and female rats post MS stress. MS stress increased protein expression of interleukin-6 (IL-6) in the medial prefrontal cortex (mPFC) and the dorsal horn of L4-L5 spinal cord segments. Intraperitoneal injection of VPA reversed MS stress-induced orofacial and somatic hyperalgesia as well as the increased expression of IL-6 in rats without sex differences. Conversely, microinjection of recombinant IL-6 protein into the mPFC or intrathecal injection reversed the analgesic effect of VPA. These results suggest that VPA may exert its therapeutic effects on orofacial and somatic hyperalgesia induced by MS through reducing IL-6 release.