Pain is a powerful motivator of behavior and it is more than the perception of nociceptive input. It is a complex experience that comprises different components: sensory discriminative, emotional-motivational and cognitive components. In chronic pain, a negative hedonic shift has been proposed that is characterized by disproportionally increased emotional-motivational compared to sensory-discriminative pain components. Such a negative hedonic shift is mirrored in a high comorbidity of chronic pain with affective disorders like depression and anxiety. However, the neurobiological mechanisms underlying such a negative hedonic shift i remain elusive. Animal work suggests an involvement of neuroinflammation, caused by chronic pain, which in turn is related to impaired release of the neurotransmitter dopamine. In line with this observation, impaired dopamine functioning has been described in chronic pain. Importantly, dopamine acts also as a neuromodulator, regulating functional connectivity between brain regions. Therefore, dysfunctional dopamine in chronic pain, possibly caused by neuroinflammation, might lead to altered functional connectivity. Correspondingly, altered functional connectivity in fronto-striatal brain networks has been shown to be predictive of transition from subacute to chronic pain. The aim of this study is to investigate the psychobiological mechanisms underlying the negative hedonic shift in chronic pain with a focus on the causal role of neuroinflammation (substudy 1) and the role of dopamine (substudy 2) in functional connectivity of fronto-striatal brain networks and their relation to heightened emotional-motivational pain processing.~A potential benefit of the study will be an increase in our knowledge on mechanisms of the development and maintenance of chronic pain in humans with a focus on emotional-motivational processes, deemed to be of very high relevance in this context. Importantly, by implementing and testing a novel conceptual framework, the results will be relevant not only to pain research but also to a broader neuroscientific community, because the expected results also relate to affective and motivational processes in other diseases (e.g. depression, anxiety, Parkinson's disease). The proposed project offers novel avenues to pain treatment based on pharmacological and psychological mechanisms-based approach instead of being symptoms-oriented as most available pain treatments at the moment.~This study entails more than minimal risks and burdens for participants, because both substudies incorporate the intake of drugs. However, both substudies comprise only low doses and/or single doses. Low-dose naltrexone (LDN) will be administered in substudy 1 for 12 weeks in chronic pain patients with fibromyalgia to down-regulate microglial activation. Previous studies indicated only very few side-effects. In substudy 2, patients with fibromyalgia and healthy participants will receive a single dose of the dopamine agonist bromocriptine (1.25 mg, p.o.) or a placebo in separate testing sessions. Healthy participants will receive in an additional testing session a single dose of the dopamine antagonist amisulpride (400 mg, p.o.). Both drugs have been repeatedly used in research with the same dosages with no or very few side effects. The methods that will be used in the experimental testing sessions are within the range of standard procedures in pain research and experimental psychology and are frequently used in healthy participants and patients. Experimental pain stimulation will be adjusted to individual pain sensitivity, rendering the applied stimulation tolerable. Magnetic resonance imaging, including spectroscopy, will be performed without a contrast medium. Peripheral venous blood sampling will be performed by an expert medical professional. The risk of unauthorized data access or unwanted identification of participants will be minimized by the use of restricted access to data and facilities, lockable cabinets, and password protected computers.~Sub-study 1:~The sample will be divided into two groups, one receiving low dose naltrexone (LDN), the other placebo for 12 weeks. Before and after this 12 week pharmacological intervention, each patient will undergo a MRI testing session at Balgrist Campus, Balgrist Hospital Zürich. A placebocontrolled design is chosen here in addition to the pre-/post-pharmacological intervention comparison, because microglia activation has been investigated only a few times in chronic pain patients so far and due to unknown possible natural variation in microglia activation.~Written consent will be obtained from each participant after explaining the purpose and the course of the experiment. At the beginning of each testing session, pain assessments will be performed, which include assessment of participants' individual heat pain threshold and tolerance. After this assessment, a blood sample will be taken to assess the erythrocyte sedimentation rate (ESR), after which participants will be positioned inside the MRI scanner for magnetic resonance spectroscopy (MRS) and to acquire fMRI (functional magnetic resonance imaging) images while participants will perform a behavioral discrimination task and an avoidance task to assess sensory-discriminative and emotional-motivational pain components. After completion of these tasks, resting state fMRI will be performed followed by a structural fMRI acquisition. Further, participants will be asked to complete some questionnaires. In addition, some trait questionnaires will be filled out during the first testing session. The duration of each of MRI testing session will be 2.5-3h.~Sub-study 2:~The sample consists of fibromyalgia patients and age- and sex-matched healthy controls. While healthy controls undergo three testing sessions to assess the effects of a dopamine receptor antagonist and agonist in comparison to placebo, fibromyalgia patients do only two testing sessions assessing only the effects of a dopamine agonist in comparison to a placebo, because for these patients the presence of a hypodopaminergic state is assumed. Thus, each session comprises the intake of a single dose of a drug or placebo and MRI scanning. Healthy controls will take in amisulpride (dopamine receptor antagonist), bromocriptine (dopamine receptor agonist), and placebo and fibromyalgia patients bromocriptine and placebo in a counterbalanced order. At the beginning of the first session, written consent will be obtained from the participants after explaining them the purpose and the course of the experiment. After intake of the capsules containing drug/placebo, there will be a waiting period to reach the peak plasma concentration of the drugs during MRI scanning. During this waiting period, participants will fill out some questionnaires. Before the MRI scanning, in each testing session, pain assessments will be performed, which includes assessment of participants individual heat pain threshold and tolerance. This will be followed by taking a blood sample to determine prolactin levels, pro-inflammatory cytokines and anti-inflammatory cytokines, neurofilaments, dopamine gene related polymorphisms after which participants will be positioned inside the MRI scanner. During MRI scanning, participants will perform a behavioral discrimination task and an avoidance task to assess sensory-discriminative and emotional-motivational pain components. After completion of these tasks, resting state fMRI will be performed followed by a structural MRI acquisition for obtaining anatomical images. The duration for each testing session is 2.5-3h.~Sample sizes for substudy 1 and 2 are based on a priori sample size calculations using G*Power 3.1 with a desired medium effect size f= 0.25, alpha = 0.05, beta= 0.95, repeated measures ANOVA within-between subject designs, and an attrition rate of 10%. Outcome variables will be analyzed in separate mixed model analyses for ANOVA designs with appropriate within- and between-subject factors. Associations of primary endpoints with questionnaire scores (secondary outcomes) will be analyzed using Pearson- or Spearman correlation coefficients, where appropriate. Significance levels will be set to 5%, adjusted with false discovery rate for multiple testing. Effect sizes will be calculated in terms of generalized eta-squared (ηG2) and Cohen's d. Spectroscopy data will be analyzed using a linear combination model. Concentrations of MI, Cho, and NAA (N-Acetyl Aspartate) will be computed using peak height relative to creatine (Cr) and compared using mixed model analyses for ANOVA designs. Images from fMRI analysis of each participant will undergo standard preprocessing (including high-pass filtering, motion correction, spatial smoothing) and will be entered into a voxel-wise analysis using a general linear model to estimate the effects of pharmacological interventions on pain-related brain activity related to emotional-motivational and sensory-discriminative pain responses. For all brain analyses, a voxel-threshold of p<0.01 and a cluster threshold for spatial extent of p<0.05 will be employed.~Within this study, pharmacological interventions, psychophysical methods, and magnetic resonance imaging will be utilized to investigate the neurobiological mechanisms involved in a negative hedonic shift in chronic pain. Low dose naltrexone will transiently down-regulate neuroinflammation in chronic pain patients. Pharmacological interventions (amisulpride and bromocriptine) will only cause a transient manipulation of dopaminergic system in both healthy controls and fibromyalgia patients. The pharmacological interventions proposed in the current study does not have a clinical intervention value, instead they are only used for the purpose of investigating psychobiological mechanisms underlying chronic pain. Psychophysical methods will allow the investigators to dissociate the emotional-motivational component of pain from its sensory discriminant component. Magnetic resonance imaging will allow the investigators to investigate brain responses and neuroinflammation in relation to chronic pain. Based on these methods, the investigators will get insights on the role of dopamine and fronto-striatal connectivity in regulating the emotional component of pain in chronic pain. The usage of the pharmacological interventions in this study hold more than minimal risks for the participants, but according to previous research studies, in which the same dosage of these pharmacologic drugs were used, only minimal side-effects have been observed (see above Risk/Benefit Assessment). Psychophysical methods and pharmacological interventions based on experimental psychology and pain research will be used in this study. These methods have been shown to be successful in investigating the different aspects of pain perception and modulation of pain perception. The methods used are in the standard range of methods from human pain research and experimental psychology. The expected results will form the basis for the development of novel mechanism-based pain therapies.
Pain is a powerful motivator of behavior and it is more than the perception of nociceptive input. It is a complex experience that comprises different components: sensory discriminative, emotional-motivational and cognitive components. In chronic pain, a negative hedonic shift has been proposed that is characterized by disproportionally increased emotional-motivational compared to sensory-discriminative pain components. Such a negative hedonic shift is mirrored in a high comorbidity of chronic pain with affective disorders like depression and anxiety. However, the neurobiological mechanisms underlying such a negative hedonic shift i remain elusive. Animal work suggests an involvement of neuroinflammation, caused by chronic pain, which in turn is related to impaired release of the neurotransmitter dopamine. In line with this observation, impaired dopamine functioning has been described in chronic pain. Importantly, dopamine acts also as a neuromodulator, regulating functional connectivity between brain regions. Therefore, dysfunctional dopamine in chronic pain, possibly caused by neuroinflammation, might lead to altered functional connectivity. Correspondingly, altered functional connectivity in fronto-striatal brain networks has been shown to be predictive of transition from subacute to chronic pain. The aim of this study is to investigate the psychobiological mechanisms underlying the negative hedonic shift in chronic pain with a focus on the causal role of neuroinflammation (substudy 1) and the role of dopamine (substudy 2) in functional connectivity of fronto-striatal brain networks and their relation to heightened emotional-motivational pain processing.