Clinical evidence suggests that pain hypersensitivity develops in patients with attention-deficit/hyperactivity disorder (ADHD). However, the mechanisms and neural circuits involved in these interactions remain unknown because of the paucity of studies in animal models. We previously validated a mouse model of ADHD obtained by neonatal 6-hydroxydopamine (6-OHDA) injection. Here, we have demonstrated that 6-OHDA mice exhibit a marked sensitization to thermal and mechanical stimuli, suggesting that phenotypes associated with ADHD include increased nociception. Moreover, sensitization to pathological inflammatory stimulus is amplified in 6-OHDA mice as compared to shams. In this ADHD model, spinal dorsal horn neuron hyperexcitability was observed. Furthermore, ADHD-related hyperactivity and anxiety, but not inattention and impulsivity, are worsened in persistent inflammatory conditions. By combining in vivo electrophysiology, optogenetics, and behavioral analyses, we demonstrated that anterior cingulate cortex (ACC) hyperactivity alters the ACC–posterior insula circuit and triggers changes in spinal networks that underlie nociceptive sensitization. Altogether, our results point to shared mechanisms underlying the comorbidity between ADHD and nociceptive sensitization. This interaction reinforces nociceptive sensitization and hyperactivity, suggesting that overlapping ACC circuits may be targeted to develop better treatments.

Recent clinical evidence suggest that pain hypersensitivity develops in subjects with attention deficit hyperactivity disorder (ADHD). However, the mechanisms and neural circuits involved in these interactions remain unknown because of the paucity of studies in animal models. In our previous work, we validated a mouse model obtained by neonatal 6-Hydroxydopamine (6-OHDA) injection, to mimic ADHD syndrome. Here, we demonstrated that 6-OHDA mice exhibited a marked decrease of withdrawal thresholds to thermal and mechanical stimuli, suggesting that ADHD conditions increase nociceptive sensitivity. Moreover, sensitization to pathological inflammatory pain is amplified in 6-OHDA mice as compared to shams. Conversely, ADHD-related hyperactivity and anxiety, but not inattention and impulsivity, are worsened in the inflammatory pain model. Our data indicated that ADHD-induced allodynia and hyperalgesia are accompanied by neuronal hyperexcitability in the dorsal spinal cord. Next, we tested the hypothesis that descending controls are responsible for pain alterations. By combining in vivo electrophysiology, optogenetic stimulation and behavioral analyses, we demonstrated that the anterior cingulate cortex (ACC) hyperactivity alters the ‘ACC – posterior insula’ circuit, and triggers changes in spinal networks that underlie pain sensitization. Altogether, our results point to unprecedented mechanisms underlying the comorbidity between ADHD and pain sensitization. They indicate that ADHD and pain sensitization are mutually worsening comorbid disorders. The identification of shared mechanisms, engaging overlapping neuronal circuits and underlying both disorders, is key to better treatments.

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