Pain hypersensitivity in a pharmacological mouse model of attention-deficit/hyperactivity disorder

Abstract

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.

P2X4 signalling contributes to hyperactivity but not pain sensitization comorbidity in a mouse model of attention deficit/hyperactivity disorder

“…Mechanical and thermal pain sensitivity were assessed with Von Frey and Plantar (Hargreaves’ method) tests, respectively ( Bouchatta et al, 2022 ).…”

“…Neuroimaging studies in ADHD patients identified structural and functional abnormalities in brain networks with a key role of the ACC ( Faraone, 2015 ) that is at the crossroad of executive functions and pain processing ( Garcia-Larrea and Peyron, 2013 ; Hart et al, 2013 ; Sellmeijer et al, 2018 ). We further identified a key role for the ACC-PI pathways in the interaction between ADHD-like conditions and pain sensitization ( Bouchatta et al, 2022 ). Therefore, we focused the present study primarily on the effects of P2X4 deletion in the ACC and on its consequences in the target PI.…”

“… 3. Plantar test (Hargreaves’method): nociceptive response to thermal stimulus was assessed using Plantar test setup (Ugo Basile, Gemonio, Italy), as described previously ( Bouchatta et al, 2022 ). During 30 min, mice were habituated to individual cages with a glass pane floor.…”

“…Because alterations of dopamine transmission are considered as significant factors for the progression of the disease ( Albrecht et al, 2015 ), a mouse model of ADHD by lesioning dopaminergic fibers with neonatal intra-cerebroventricular injection of 6-hydroxydopamine (6-OHDA) was developed and validated ( Sontag et al, 2010 ; Bouchatta et al, 2018 ; 2020 ). In addition to hyperactivity, inattention and impulsivity, the 6-OHDA mice exhibited a marked decrease of withdrawal thresholds to thermal and mechanical stimuli, suggesting that ADHD-like conditions increase nociceptive sensitivity ( Bouchatta et al, 2022 ; Meseguer-Beltrán et al, 2023 ; Sifeddine et al, 2023 ). These previous studies indicated that ADHD and pain sensitization are mutually worsening comorbid disorders.…”

“…These previous studies indicated that ADHD and pain sensitization are mutually worsening comorbid disorders. They also pointed to a key role of the anterior cingulate cortex (ACC) hyperactivity that alters the ‘ACC–posterior insula (PI)’ circuit, and triggers pain sensitization ( Bouchatta et al, 2022 ).…”