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 CRY1 (c. 1657 + 3A > C), which leads to deletion of exon 11 expression in the CRY1 protein (CRY1Δ11), exhibit ADHD symptoms. Here, we demonstrate that the responses to thermal and mechanical stimuli were amplified in the Cry1Δ11 mice. RNA-sequencing analysis identified protein kinase A (PKA) signaling as being overactive in the spinal cords of Cry1Δ11 mice. The neuronal excitability was significantly enhanced in the spinal cords of Cry1Δ11 mice as determined by in vitro electrophysiology. The PKA inhibitor H89 normalized hyperalgesia in Cry1Δ11 mice, underscoring the causative effect of overactive PKA signaling. 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.