The primary study aim is to unravel the nature of impaired pain inhibition during exercise in patients with chronic Whiplash-Associated Disorders (WAD). This will be ascertained by examining whether activation of serotonergic and/or noradrenergic descending pathways improves pain inhibition during exercise in these patients. In addition, it is aimed at examining whether activation of serotonergic and/or noradrenergic descending pathways prevents post-exertional malaise following submaximal exercise in chronic WAD patients. A secondary study aim comprises of examining the effect of an acute submaximal exercise with and without activation of serotonergic or noradrenergic descending pathways on chronic WAD patients' cognitive performance. Furthermore, the isolated effect of activated serotonergic and noradrenergic descending pathways on chronic WAD patients' cognitive performance will be studied.

Chronic Whiplash-Associated Disorders (WAD) is a debilitating, costly condition, and remains a challenge for clinicians, including physicians, rehabilitation specialists and physiotherapists. There is now consistent evidence for central sensitization in people with chronic WAD. In a previous study in chronic WAD patients, our group showed that pain inhibition during exercise is impaired and that a submaximal exercise triggers a severe relapse named post-exertional malaise. On the other hand, imbalance of serotonin (5-HT) and norepinephrine (NE) is likely to be responsible for malfunctioning of pain inhibitory pathways. Indeed, NE is required for activation of descending noradrenergic pathways with established nociceptive inhibitory properties. Serotonin reuptake inhibitor drugs activate serotonergic descending pathways that recruit, in part, opioid peptide-containing interneurons in the dorsal horn. It becomes more and more clear that the lack of pain inhibition accounts in part for various symptoms at rest and following exercise in particular (post-exertional malaise). However, the mechanisms behind the lack of pain inhibition during exercise remain to be revealed. Besides the lack of endogenous pain inhibition during exercise in people with chronic WAD, there appears to be sufficient evidence to support the presence of impaired cognitive function in chronic pain patients in general and preliminary evidence in chronic WAD patients in particular.

The present study aimed at examining whether activation of serotonergic and/or noradrenergic descending pathways improves pain inhibition during exercise in chronic WAD patients. In addition, it is aimed at examining whether activation of serotonergic and/or noradrenergic descending pathways prevents post-exertional malaise following submaximal exercise in these patients. A secondary study aim comprises of examining the effect of an acute submaximal exercise with and without activation of serotonergic or noradrenergic descending pathways on chronic WAD patients' cognitive performance. Furthermore, the isolated effect of activated serotonergic and noradrenergic descending pathways on chronic WAD patients' cognitive performance will be studied.We will modulate endogenous serotonergic and adrenergic pain inhibitory mechanisms by using a selective NE reuptake inhibitor (NRI) and a selective 5-HT reuptake inhibitor (SSRI). Endogenous pain inhibition and cognitive function (sustained and selective attention, and executive function) will be studied at rest and in response to exercise (1) under baseline condition, (2) after the intake of a NRI (Atomoxetine), and (3) after the intake of a SSRI (Citalopram).

Inclusion Criteria for patients:

• WAD grades I to III according to the Quebec Task Force criteria
• experienced a whiplash trauma at least three months ago
• with chronic pain as a result of a whiplash injury
• 18-65 years of age and with Dutch as their native language will be able to participate

Exclusion Criteria for patients:

• other comorbidities or health issues that could explain the pain complaints
• < 18years > 65 years
• pregnant or until 1 year postnatal (for women)
• use of anti-depressive, anti-epileptic and pain medication.

Inclusion Criteria for healthy volunteers:

• 18-65 years of age and with Dutch as their native language will be able to participate
• having a sedentary job and doing < 3 h moderate physical activity/week
• being painfree without any chronic disease

Exclusion Criteria for healthy volunteers:

• < 18years > 65 years
• pregnant or until 1 year postnatal (for women)
• use of anti-depressive, anti-epileptic and pain medication.

WAD patients: primary care clinic & community sample Healthy people: community sample