Effect of atomoxetine on ADHD-pain hypersensitization comorbidity in 6-OHDA lesioned mice

Pharmacol Rep. 2023 Apr;75(2):342-357. doi: 10.1007/s43440-023-00459-3. Epub 2023 Feb 14.


Background: Methylphenidate and atomoxetine are used for the treatment of attention-deficit/hyperactivity disorder (ADHD). Our previous studies established the validity of the 6-hydroxydopamine (6-OHDA) mouse model of ADHD and demonstrated hypersensitivity to pain, in line with clinical reports in ADHD patients. Acute methylphenidate treatment reduces hyperactivity and increases attention, but does not affect pain behaviors in this mouse model. Whereas atomoxetine has been shown to be effective against some symptoms of ADHD, nothing is known about its possible action on comorbid pain hypersensitivity. The objectives of the present research are (1) to investigate the effects of acute and chronic treatment with atomoxetine on ADHD-like symptoms and nociceptive thresholds, and (2) to explore the catecholaminergic systems underlying these effects.

Methods: Sham and 6-OHDA cohorts of male mice were tested for hyperactivity (open field), attention and impulsivity (5-choice serial reaction time task test), and thermal (hot plate test) and mechanical (von Frey test) thresholds after acute or repeated treatment with vehicle or atomoxetine (1, 3 or 10 mg/kg).

Results: Acute administration of atomoxetine (10 mg/kg) reduced the hyperactivity and impulsivity displayed by 6-OHDA mice, without affecting attention or nociception. However, atomoxetine administered at 3 mg/kg/day for 7 days alleviated the ADHD-like core symptoms and attenuated the hyperalgesic responses. Furthermore, hyperlocomotion and anti-hyperalgesic activity were antagonized with phentolamine, propranolol, and sulpiride pre-treatments.

Conclusion: These findings demonstrated that when administered chronically, atomoxetine has a significant effect on ADHD-associated pain hypersensitization, likely mediated by both α- and β-adrenergic and D2/D3 dopaminergic receptors, and suggest new indications for atomoxetine that will need to be confirmed by well-designed clinical trials.

Keywords: ADHD; Atomoxetine; Dopaminergic receptors; Pain; α-Adrenergic receptors; β-Adrenergic receptors.

MeSH terms

  • Adrenergic Uptake Inhibitors / adverse effects
  • Animals
  • Atomoxetine Hydrochloride / pharmacology
  • Atomoxetine Hydrochloride / therapeutic use
  • Attention Deficit Disorder with Hyperactivity* / chemically induced
  • Attention Deficit Disorder with Hyperactivity* / drug therapy
  • Comorbidity
  • Male
  • Methylphenidate*
  • Mice
  • Oxidopamine
  • Pain / drug therapy
  • Propylamines / pharmacology


  • Atomoxetine Hydrochloride
  • Oxidopamine
  • Propylamines
  • Methylphenidate
  • Adrenergic Uptake Inhibitors