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

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Abstract

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.

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Data availability

The datasets generated during the current study are available from the corresponding author upon reasonable request from qualified researchers.

Abbreviations

5-CSRTT:

5-Choice serial reaction time task

6-OHDA:

6-Hydroxydopamine

ACC:

Anterior cingulate cortex

ADHD:

Attention-deficit/hyperactivity disorder

ATX:

Atomoxetine

CPP:

Conditioned place preference

EPM:

Elevated plus maze

ip :

Intraperitoneal

ITI:

Inter-trial interval

LC:

Locus coeruleus

OF:

Open field

PFC:

Prefrontal cortex

PND5:

Postnatal day 5

sc :

Subcutaneous

SEM:

Standard error of the mean

References

  1. Barkley RA. Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychol Bull. 1997;121(1):65–94.

    Article  PubMed  Google Scholar 

  2. Biederman J, Faraone SV. Attention-deficit hyperactivity disorder [published correction appears in Lancet. 2006 Jan 21;367(9506):210]. Lancet. 2005;366(9481):237–48.

    Article  PubMed  Google Scholar 

  3. Kessler RC, Adler L, Barkley R, Biederman J, Conners CK, Demler O, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry. 2006;163(4):716–23.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Durston S. A review of the biological bases of ADHD: what have we learned from imaging studies? Ment Retard Dev Disabil Res Rev. 2003;9(3):184–95.

    Article  PubMed  Google Scholar 

  5. Faraone SV, Asherson P, Banaschewski T, Biederman J, Buitelaar JK, Ramos-Quiroga JA, et al. Attention-deficit/hyperactivity disorder. Nat Rev Dis Primers. 2015;1:15020.

    Article  PubMed  Google Scholar 

  6. Tripp G, Wickens JR. Neurobiology of ADHD. Neuropharmacology. 2009;57(7–8):579–89.

    Article  CAS  PubMed  Google Scholar 

  7. Faraone SV, Buitelaar J. Comparing the efficacy of stimulants for ADHD in children and adolescents using meta-analysis. Eur Child Adolesc Psychiatry. 2010;19(4):353–64.

    Article  PubMed  Google Scholar 

  8. Spencer T, Biederman J, Wilens T. Nonstimulant treatment of adult attention-deficit/hyperactivity disorder. Psychiatr Clin North Am. 2004;27(2):373–83.

    Article  PubMed  Google Scholar 

  9. Bagot KS, Kaminer Y. Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: a systematic review. Addiction. 2014;109(4):547–57.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Lakhan SE, Kirchgessner A. Prescription stimulants in individuals with and without attention deficit hyperactivity disorder: misuse, cognitive impact, and adverse effects. Brain Behav. 2012;2(5):661–77.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Morton WA, Stockton GG. Methylphenidate abuse and psychiatric side effects. Prim Care Companion J Clin Psychiatry. 2000;2(5):159–64.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Wilens TE, Biederman J, Spencer TJ. Attention deficit/hyperactivity disorder across the lifespan. Annu Rev Med. 2002;53:113–31.

    Article  CAS  PubMed  Google Scholar 

  13. Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, et al. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology. 2002;27(5):699–711.

    Article  CAS  PubMed  Google Scholar 

  14. Michelson D, Faries D, Wernicke J, Kelsey D, Kendrick K, Sallee FR, et al. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study. Pediatrics. 2001;108(5):E83.

    Article  CAS  PubMed  Google Scholar 

  15. Bouchatta O, Manouze H, Bouali-Benazzouz R, Kerekes N, Ba-M’hamed S, Fossat P, et al. Neonatal 6-OHDA lesion model in mouse induces attention-deficit/ hyperactivity disorder (ADHD)-like behaviour. Sci Rep. 2018;8(1):15349.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Stray LL, Kristensen Ø, Lomeland M, Skorstad M, Stray T, Tønnessen FE. Motor regulation problems and pain in adults diagnosed with ADHD. Behav Brain Funct. 2013;9:18.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Treister R, Eisenberg E, Demeter N, Pud D. Alterations in pain response are partially reversed by methylphenidate (Ritalin) in adults with attention deficit hyperactivity disorder (ADHD). Pain Pract. 2015;15(1):4–11.

    Article  PubMed  Google Scholar 

  18. Wolff N, Rubia K, Knopf H, Hölling H, Martini J, Ehrlich S, et al. Reduced pain perception in children and adolescents with ADHD is normalized by methylphenidate. Child Adolesc Psychiatry Ment Health. 2016;10:24.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Bouchatta O, Aby F, Sifeddine W, Bouali-Benazzouz R, Brochoire L, Manouze H, et al. Pain hypersensitivity in a pharmacological mouse model of attention-deficit/hyperactivity disorder. Proc Natl Acad Sci USA. 2022;119(30): e2114094119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hoshino H, Obata H, Nakajima K, Mieda R, Saito S. The antihyperalgesic effects of intrathecal bupropion, a dopamine and noradrenaline reuptake inhibitor, in a rat model of neuropathic pain. Anesth Analg. 2015;120(2):460–6.

    Article  CAS  PubMed  Google Scholar 

  21. Hiroki T, Suto T, Saito S, Obata H. Repeated administration of amitriptyline in neuropathic pain: modulation of the noradrenergic descending inhibitory system. Anesth Analg. 2017;125(4):1281–8.

    Article  CAS  PubMed  Google Scholar 

  22. Obata H. Analgesic mechanisms of antidepressants for neuropathic pain. Int J Mol Sci. 2017;18(11):2483.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Baune BT, Wiede F, Braun A, Golledge J, Arolt V, Koerner H. Cognitive dysfunction in mice deficient for TNF- and its receptors. Am J Med Genet B Neuropsychiatr Genet. 2008;147B(7):1056–64.

    Article  CAS  PubMed  Google Scholar 

  24. Patel S, Stolerman IP, Asherson P, Sluyter F. Attentional performance of C57BL/6 and DBA/2 mice in the 5-choice serial reaction time task. Behav Brain Res. 2006;170(2):197–203.

    Article  CAS  PubMed  Google Scholar 

  25. Kwan KY, Allchorne AJ, Vollrath MA, Christensen AP, Zhang DS, Woolf CJ, et al. TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction. Neuron. 2006;50(2):277–89.

    Article  CAS  PubMed  Google Scholar 

  26. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994;53(1):55–63.

    Article  CAS  PubMed  Google Scholar 

  27. Zhu J, Spencer TJ, Liu-Chen LY, Biederman J, Bhide PG. Methylphenidate and μ opioid receptor interactions: a pharmacological target for prevention of stimulant abuse. Neuropharmacology. 2011;61(1–2):283–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ogata M, Noda K, Akita H, Ishibashi H. Characterization of nociceptive response to chemical, mechanical, and thermal stimuli in adolescent rats with neonatal dopamine depletion. Neuroscience. 2015;289:43–55.

    Article  CAS  PubMed  Google Scholar 

  29. Piña R, Rozas C, Contreras D, Hardy P, Ugarte G, Zeise ML, et al. Atomoxetine reestablishes long term potentiation in a mouse model of attention deficit/hyperactivity disorder. Neuroscience. 2020;439:268–74.

    Article  PubMed  Google Scholar 

  30. A, Micale V, Mazzola C, Salomone S, Drago F. The selective norepinephrine reuptake inhibitor atomoxetine counteracts behavioral impairments in trimethyltin-intoxicated rats. Eur J Pharmacol. 2012;683(1–3):148–154.

  31. Moran-Gates T, Zhang K, Baldessarini RJ, Tarazi FI. Atomoxetine blocks motor hyperactivity in neonatal 6-hydroxydopamine-lesioned rats: implications for treatment of attention-deficit hyperactivity disorder. Int J Neuropsychopharmacol. 2005;8(3):439–44.

    Article  CAS  PubMed  Google Scholar 

  32. Turner M, Wilding E, Cassidy E, Dommett EJ. Effects of atomoxetine on locomotor activity and impulsivity in the spontaneously hypertensive rat. Behav Brain Res. 2013;243:28–37.

    Article  CAS  PubMed  Google Scholar 

  33. Moon SJ, Kim CJ, Lee YJ, Hong M, Han J, Bahn GH. Effect of atomoxetine on hyperactivity in an animal model of attention-deficit/hyperactivity disorder (ADHD). PLoS ONE. 2014;9(10): e108918.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Navarra R, Graf R, Huang Y, et al. Effects of atomoxetine and methylphenidate on attention and impulsivity in the 5-choice serial reaction time test. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(1):34–41.

    Article  CAS  PubMed  Google Scholar 

  35. Robinson ES, Eagle DM, Mar AC, Bari A, Banerjee G, Jiang X, et al. Similar effects of the selective noradrenaline reuptake inhibitor atomoxetine on three distinct forms of impulsivity in the rat. Neuropsychopharmacology. 2008;33(5):1028–37.

    Article  CAS  PubMed  Google Scholar 

  36. Pillidge K, Porter AJ, Vasili T, Heal DJ, Stanford SC. Atomoxetine reduces hyperactive/impulsive behaviours in neurokinin-1 receptor “knockout” mice. Pharmacol Biochem Behav. 2014;127:56–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ansquer S, Belin-Rauscent A, Dugast E, Duran T, Benatru I, Mar AC, et al. Atomoxetine decreases vulnerability to develop compulsivity in high impulsive rats. Biol Psychiatry. 2014;75(10):825–32.

    Article  CAS  PubMed  Google Scholar 

  38. Sun H, Cocker PJ, Zeeb FD, Winstanley CA. Chronic atomoxetine treatment during adolescence decreases impulsive choice, but not impulsive action, in adult rats and alters markers of synaptic plasticity in the orbitofrontal cortex. Psychopharmacology. 2012;219(2):285–301.

    Article  CAS  PubMed  Google Scholar 

  39. Baarendse PJ, Vanderschuren LJ. Dissociable effects of monoamine reuptake inhibitors on distinct forms of impulsive behavior in rats. Psychopharmacology. 2012;219(2):313–26.

    Article  CAS  PubMed  Google Scholar 

  40. Robinson ES. Blockade of noradrenaline re-uptake sites improves accuracy and impulse control in rats performing a five-choice serial reaction time tasks. Psychopharmacology. 2012;219(2):303–12.

    Article  CAS  PubMed  Google Scholar 

  41. Wilens TE, Newcorn JH, Kratochvil CJ, et al. Long-term atomoxetine treatment in adolescents with attention-deficit/hyperactivity disorder. J Pediatr. 2006;149(1):112–9.

    Article  CAS  PubMed  Google Scholar 

  42. Hazell PL, Kohn MR, Dickson R, Walton RJ, Granger RE, Wyk GW. Core ADHD symptom improvement with atomoxetine versus methylphenidate: a direct comparison meta-analysis. J Atten Disord. 2011;15(8):674–83.

    Article  PubMed  Google Scholar 

  43. Chan E, Fogler JM, Hammerness PG. Treatment of attention-deficit/hyperactivity disorder in adolescents: a systematic review. JAMA. 2016;315(18):1997–2008.

    Article  CAS  PubMed  Google Scholar 

  44. Vorobeychik Y, Acquadro MA. Use of atomoxetine in a patient with fibromyalgia syndrome and attention-deficit hyperactivity disorder. J Musculoskelet Pain. 2008;16:189–92.

    Article  Google Scholar 

  45. Barbaros MB, Can ÖD, Üçel Uİ, Turan Yücel N, Demir ÖÜ. Antihyperalgesic activity of atomoxetine on diabetes-induced neuropathic pain: contribution of noradrenergic and dopaminergic systems. Molecules. 2018;23(8):2072.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Mesdaghinia A, Banafshe H, Moravveji A, Hajiagajani G, Esmaeilian N, Abed A. Anti-nociceptive effect of atomoxetine on paclitaxel-induced neuropathic pain in mice and role of alpha-2 adrenergic receptor. FEYZ. 2022;26(1):1–8.

    Google Scholar 

  47. Khoodoruth MAS, Ouanes S, Khan YS. A systematic review of the use of atomoxetine for management of comorbid anxiety disorders in children and adolescents with attention-deficit hyperactivity disorder. Res Dev Disabil. 2022;128: 104275.

    Article  PubMed  Google Scholar 

  48. Geller D, Donnelly C, Lopez F, et al. Atomoxetine treatment for pediatric patients with attention-deficit/hyperactivity disorder with comorbid anxiety disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(9):1119–27.

    Article  PubMed  Google Scholar 

  49. Adler LA, Liebowitz M, Kronenberger W, et al. Atomoxetine treatment in adults with attention-deficit/hyperactivity disorder and comorbid social anxiety disorder. Depress Anxiety. 2009;26(3):212–21.

    Article  CAS  PubMed  Google Scholar 

  50. Marchant BK, Reimherr FW, Halls C, Williams ED, Strong RE, Kondo D, et al. Long-term open-label response to atomoxetine in adult ADHD: influence of sex, emotional dysregulation, and double-blind response to atomoxetine. Atten Defic Hyperact Disord. 2011;3(3):237–44.

    Article  PubMed  Google Scholar 

  51. Goto T, Hirata Y, Takita Y, Trzepacz PT, Allen AJ, Song DH, et al. Efficacy and safety of atomoxetine hydrochloride in Asian adults with ADHD. J Atten Disord. 2017;21(2):100–9.

    Article  PubMed  Google Scholar 

  52. Udvardi PT, Föhr KJ, Henes C, Liebau S, Dreyhaupt J, Boeckers TM, et al. Atomoxetine affects transcription/translation of the NMDA receptor and the norepinephrine transporter in the rat brain–an in vivo study. Drug Des Dev Ther. 2013;7:1433–46.

    Google Scholar 

  53. dela Peña IC, Ahn HS, Ryu JH, Shin CY, Park IH, Cheong JH. Conditioned place preference studies with atomoxetine in an animal model of ADHD: effects of previous atomoxetine treatment. Eur J Pharmacol. 2011;667(1–3):238–41.

    Article  PubMed  Google Scholar 

  54. Wee S, Woolverton WL. Evaluation of the reinforcing effects of atomoxetine in monkeys: comparison to methylphenidate and desipramine. Drug Alcohol Depend. 2004;75(3):271–6.

    Article  CAS  PubMed  Google Scholar 

  55. Heil SH, Holmes HW, Bickel WK, Higgins ST, Badger GJ, Laws HF, et al. Comparison of the subjective, physiological, and psychomotor effects of atomoxetine and methylphenidate in light drug users. Drug Alcohol Depend. 2002;67(2):149–56.

    Article  CAS  PubMed  Google Scholar 

  56. Lile JA, Stoops WW, Durell TM, Glaser PE, Rush CR. Discriminative-stimulus, self-reported, performance, and cardiovascular effects of atomoxetine in methylphenidate-trained humans. Exp Clin Psychopharmacol. 2006;14(2):136–47.

    Article  CAS  PubMed  Google Scholar 

  57. Wilens TE, Adler LA, Weiss MD, Michelson D, Ramsey JL, Moore RJ, et al. Atomoxetine treatment of adults with ADHD and comorbid alcohol use disorders. Drug Alcohol Depend. 2008;96(1–2):145–54.

    Article  CAS  PubMed  Google Scholar 

  58. Swanson CJ, Perry KW, Koch-Krueger S, Katner J, Svensson KA, Bymaster FP. Effect of the attention deficit/hyperactivity disorder drug atomoxetine on extracellular concentrations of norepinephrine and dopamine in several brain regions of the rat. Neuropharmacology. 2006;50(6):755–60.

    Article  CAS  PubMed  Google Scholar 

  59. Childress AC, Sallee FR. Attention-deficit/hyperactivity disorder with inadequate response to stimulants: approaches to management. CNS Drugs. 2014;28(2):121–9.

    Article  CAS  PubMed  Google Scholar 

  60. Hunt RD, Arnsten AF, Asbell MD. An open trial of guanfacine in the treatment of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1995;34(1):50–4.

    Article  CAS  PubMed  Google Scholar 

  61. Ma CL, Arnsten AF, Li BM. Locomotor hyperactivity induced by blockade of prefrontal cortical alpha2-adrenoceptors in monkeys. Biol Psychiatry. 2005;57(2):192–5.

    Article  CAS  PubMed  Google Scholar 

  62. Frances H, Puech AJ, Danti S, Simon P. Attempt at pharmacological differentiation of central beta-adrenergic receptors. Eur J Pharmacol. 1983;92(3–4):223–30.

    Article  CAS  PubMed  Google Scholar 

  63. Martin P, Soubrié P, Simon P. Comparative study of the effects of stimulation or blockade of beta-adrenoceptors on the head-twitches induced in mice by 5-hydroxytryptophan versus 5-methoxy-N,N-dimethyltryptamine. J Pharmacol. 1986;17(2):119–25.

    CAS  PubMed  Google Scholar 

  64. O’Donnell JM. Reduced locomotor activity of rats mediated by peripheral beta adrenergic receptors. Res Commun Chem Pathol Pharmacol. 1993;82(3):375–8.

    CAS  PubMed  Google Scholar 

  65. Arnsten AF, Li BM. Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions. Biol Psychiatry. 2005;57(11):1377–84.

    Article  CAS  PubMed  Google Scholar 

  66. Dalley JW, Cardinal RN, Robbins TW. Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates. Neurosci Biobehav Rev. 2004;28(7):771–84.

    Article  CAS  PubMed  Google Scholar 

  67. Frazer A. Serotonergic and noradrenergic reuptake inhibitors: prediction of clinical effects from in vitro potencies. J Clin Psychiatry. 2001;62(Suppl 12):16–23.

    CAS  PubMed  Google Scholar 

  68. Bari A, Aston-Jones G. Atomoxetine modulates spontaneous and sensory-evoked discharge of locus coeruleus noradrenergic neurons. Neuropharmacology. 2013;64(1):53–64.

    Article  CAS  PubMed  Google Scholar 

  69. Franowicz JS, Arnsten AF. The alpha-2a noradrenergic agonist, guanfacine, improves delayed response performance in young adult rhesus monkeys. Psychopharmacology. 1998;136(1):8–14.

    Article  CAS  PubMed  Google Scholar 

  70. Ramos BP, Arnsten AF. Adrenergic pharmacology and cognition: focus on the prefrontal cortex. Pharmacol Ther. 2007;113(3):523–36.

    Article  CAS  PubMed  Google Scholar 

  71. Bari A, Dalley JW, Robbins TW. The application of the 5-choice serial reaction time task for the assessment of visual attentional processes and impulse control in rats. Nat Protoc. 2008;3(5):759–67.

    Article  CAS  PubMed  Google Scholar 

  72. De Martino B, Strange BA, Dolan RJ. Noradrenergic neuromodulation of human attention for emotional and neutral stimuli. Psychopharmacology. 2008;197(1):127–36.

    Article  PubMed  Google Scholar 

  73. Pattij T, Schetters D, Schoffelmeer AN, van Gaalen MM. On the improvement of inhibitory response control and visuospatial attention by indirect and direct adrenoceptor agonists. Psychopharmacology. 2012;219(2):327–40.

    Article  CAS  PubMed  Google Scholar 

  74. Strange BA, Dolan RJ. Beta-adrenergic modulation of oddball responses in humans. Behav Brain Funct. 2007;3:29.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Fernando AB, Economidou D, Theobald DE, Zou MF, Newman AH, Spoelder M, et al. Modulation of high impulsivity and attentional performance in rats by selective direct and indirect dopaminergic and noradrenergic receptor agonists. Psychopharmacology. 2012;219(2):341–52.

    Article  CAS  PubMed  Google Scholar 

  76. Moreno M, Economidou D, Mar AC, López-Granero C, Caprioli D, Theobald DE, et al. Divergent effects of D2/3 receptor activation in the nucleus accumbens core and shell on impulsivity and locomotor activity in high and low impulsive rats. Psychopharmacology. 2013;228(1):19–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Pardey MC, Kumar NN, Goodchild AK, Cornish JL. Catecholamine receptors differentially mediate impulsive choice in the medial prefrontal and orbitofrontal cortex. J Psychopharmacol. 2013;27(2):203–12.

    Article  CAS  PubMed  Google Scholar 

  78. Pezze MA, Dalley JW, Robbins TW. Differential roles of dopamine D1 and D2 receptors in the nucleus accumbens in attentional performance on the five-choice serial reaction time task. Neuropsychopharmacology. 2007;32(2):273–83.

    Article  CAS  PubMed  Google Scholar 

  79. Ito S, Suto T, Saito S, Obata H. Repeated administration of duloxetine suppresses neuropathic pain by accumulating effects of noradrenaline in the spinal cord. Anesth Analg. 2018;126(1):298–307.

    Article  CAS  PubMed  Google Scholar 

  80. Sudo RT, do Amaral RV, Monteiro C, Pitta I, Lima M, Montes GC, et al. Antinociception induced by a novel α2A adrenergic receptor agonist in rodents acute and chronic pain models. Eur J Pharmacol. 2017;815:210–8.

    Article  CAS  PubMed  Google Scholar 

  81. Kim W, Chung Y, Choi S, Min BI, Kim SK. Duloxetine protects against oxaliplatin-induced neuropathic pain and spinal neuron hyperexcitability in rodents. Int J Mol Sci. 2017;18(12):2626.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Potvin S, Grignon S, Marchand S. Human evidence of a supra-spinal modulating role of dopamine on pain perception. Synapse. 2009;63(5):390–402.

    Article  CAS  PubMed  Google Scholar 

  83. Taniguchi W, Nakatsuka T, Miyazaki N, Yamada H, Takeda D, Fujita T, et al. In vivo patch-clamp analysis of dopaminergic antinociceptive actions on substantia gelatinosa neurons in the spinal cord. Pain. 2011;152(1):95–105.

    Article  CAS  PubMed  Google Scholar 

  84. Chen M, Hoshino H, Saito S, Yang Y, Obata H. Spinal dopaminergic involvement in the antihyperalgesic effect of antidepressants in a rat model of neuropathic pain. Neurosci Lett. 2017;649:116–23.

    Article  CAS  PubMed  Google Scholar 

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Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. This research is supported by the sources of the Faculty of Sciences Semlalia, Cadi Ayyad University, Marrakesh, Morocco.

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WS, SBM, ML and MB conceived, and designed the experiments, WS performed the behavioral experiments, SBM, MB, and ML supervised the experiments, methodology, analysis, and writing the original draft. All the authors discussed and revised the manuscript.

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Correspondence to Mohamed Bennis.

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Sifeddine, W., Ba-M’hamed, S., Landry, M. et al. Effect of atomoxetine on ADHD-pain hypersensitization comorbidity in 6-OHDA lesioned mice. Pharmacol. Rep 75, 342–357 (2023). https://doi.org/10.1007/s43440-023-00459-3

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