A 11C raclopride PET study of dopamine activity, pain perception and reward processes in patients with fibromyalgia

Abstract

Findings suggest that pain and reward are mediated by similar neural pathways in the central nervous system (CNS) and that these pathways are related to both the dopamine (DA) and opioid system. While DA has well described roles in motivational states, reward processing and motor functions, a role for dopaminergic neurotransmission in modulating pain perception and natural analgesia has also been demonstrated. Striatal dopaminergic neurotransmission has been found to be altered in chronic pain syndromes such as burning mouth, atypical facial pain and Fibromyalgia syndrome (FMS). FMS is a chronic, painful musculoskeletal disorder characterized by widespread pain, disturbed non restorative sleep, fatigue, and cognitive alterations and an increased incidence of depressive symptoms. The neuropathophysiology of FMS is still poorly understood. Based on the proposition that a disruption of normal dopaminergic neurotransmission may make a substantial contribution to the pathophysiology of FMS, the prevailing motive for this project was to investigate the modulation of pain perception by DA in FMS patients compared to healthy controls using the [11C] raclopride Positron Emission Tomography (PET) method. Because chronic pain has been suggested to impair reward processing and because FMS is often associated with depression - a condition in which the neural processing of rewards has been shown to be disabled, we tested whether the dopaminergic responses to financial rewards were impaired in FMS and whether this impairment could differentiate between FMS patients with and without depression. We investigated DA D2/D3 receptor availability at rest and subjective ratings of pain related to the administration of painful thermal stimulation in 17 healthy subjects, 13 subjects fulfilling the American College of Rheumatology (ACR) classification criteria for FMS without psychiatric comorbidity, and 11 subjects meeting the ACR criteria for FMS and the criteria for major depressive disorder (MDD) (Report 1). Additionally, we measured the endogenous DA release associated with unpredictable monetary rewards during Bolus-plus- Infusion [11C] raclopride PET scanning in the same population (Report 2). Findings from report 1 surprisingly revealed no differences in striatal D2/D3 receptor availability between FMS patients with and without co-morbid MDD compared to healthy controls. Furthermore, different associations between D2/D3 receptor availability and pain perception were found between FMS patients and healthy subjects. Our results suggested that alterations in the dopaminergic system appear to be linked to pain sensitivity and secondly, that depression could influence pain perception in FMS patients. Report 2 provided evidence for increased DA release to unpredictable monetary rewards in FMS patients compared to healthy controls which was more prominent in FMS patients with co-morbid depression. These results suggested dysfunctional DA responses to monetary rewards in FMS patients relative to healthy controls and that the dysfunctional reward circuitry could be associated with co-morbid depression in the pathology of FMS. This work presents compelling evidence for alterations in the dopaminergic system as well as dysfunctional DA responses to monetary rewards in FMS. These findings provide further insight into the neuropathophysiology of FMS by addressing common neural bases of FMS and depression.