Overactive PKA signaling underlies the hyperalgesia in an ADHD mouse model

There is an intimate relationship between pain hypersensitivity and attention deficit hyperactivity disorder (ADHD); however, the underlying mechanisms are still elusive. Individuals carrying the mutation in a circadian core gene, CRY1 (c. 1657 + 3A > C), which leads to deletion of exon 11 expression in the CRY1 protein (CRY1delta11), exhibit ADHD symptoms. We previously reported ADHD-like phenotypes in mice with the Cry1delta11 mutation. Here, we demonstrate that the responses to thermal and mechanical stimuli were amplified in the Cry1delta11 mice compared to wild-type controls. RNA-sequencing analysis identified PKA signaling as being overactive in the spinal cords of Cry1delta11 mice; and this result was verified by Western blotting and immunohistochemistry. Consequently, neuronal excitability was significantly enhanced in the spinal cords of Cry1delta11 mice as determined by in vitro electrophysiology. The PKA inhibitor H89 normalized hyperalgesia in Cry1delta11 mice, underscoring the causative effect of overactive PKA signaling. Phosphorylation of a panel of proteins was altered in the spinal cords of Cry1delta11 mice; some of these proteins were involved in pain sensation. Our results thus point to the PKA signaling pathway as the underlying mechanism and a potential therapeutic target for pain hypersensitivity in a validated ADHD mouse model.