Susanne Becker

Mesolimbic dopamine signaling in acute and chronic pain: implications for motivation, analgesia, and addiction.

The mesolimbic dopamine system comprises neurons in the ventral tegmental area (VTA) and substantia nigra (SN), projecting to the ventral striatum. This system was originally described to mediate pleasure and goal-directed movement associated with rewarding stimuli.70 However, it is now clear that dopamine, although crucial for reward processing, drives not the hedonic experience of reward (“liking”) but rather the instrumental behavior of reward-driven actions (“wanting”).6 Phasic dopamine acts as an incentive salience signal underlying reinforcement learning.57,59 Moreover, aversive stimuli, such as pain, also stimulate dopamine, further diminishing the idea of dopamine as a “reward” signal.9,10 Recent studies suggest that dopamine neurons in the VTA and SN form a heterogeneous population tuned to either (or both) aversive or rewarding stimuli.3,8,30,39 This review will summarize our current understanding of the role of the mesolimbic dopamine system in acute pain and the changes that occur in chronic pain.

Dysfunctional Neurotransmitter Systems in Fibromyalgia, Their Role in Central Stress Circuitry and Pharmacological Actions on These Systems

Fibromyalgia is considered a stress-related disorder, and hypo- as well as hyperactive stress systems (sympathetic nervous system and hypothalamic-pituitary-adrenal axis) have been found. Some observations raise doubts on the view that alterations in these stress systems are solely responsible for fibromyalgia symptoms. Cumulative evidence points at dysfunctional transmitter systems that may underlie the major symptoms of the condition. In addition, all transmitter systems found to be altered in fibromyalgia influence the bodys stress systems. Since both transmitter and stress systems change during chronic stress, it is conceivable that both systems change in parallel, interact, and contribute to the phenotype of fibromyalgia. As we outline in this paper, subgroups of patients might exhibit varying degrees and types of transmitter dysfunction, explaining differences in symptomatoloy and contributing to the heterogeneity of fibromyalgia. The finding that not all fibromyalgia patients respond to the same medications, targeting dysfunctional transmitter systems, further supports this hypothesis.

Pain increases motivational drive to obtain reward, but does not affect associated hedonic responses: A behavioural study in healthy volunteers

Pain and reward have been suggested to interact, and some evidence is provided by a rodent study showing that acutely injured animals are more motivated to reach a food reward while they do not increase food consumption, pointing at unaltered reward liking. Since no data exist in humans, we conducted a psychophysical experiment to test the effects of experimentally induced tonic pain on (1) the motivation to receive reward and (2) hedonic responses when being rewarded.

Operant learning of perceptual sensitization and habituation is impaired in fibromyalgia patients with and without irritable bowel syndrome.

&NA; The important role of operant learning in the development and maintenance of chronic pain is widely recognized. A specific type of reinforcement based on the reduction of painful stimulation when a person’s perception changes in the desired direction has been termed intrinsic reinforcement of pain. In the present study, the role of intrinsic operant learning in chronic pain was tested in fibromyalgia (FM) patients with and without comorbid irritable bowel syndrome (IBS) compared with healthy persons. A previously established operant learning task was used to enhance perceptual sensitization or habituation through intrinsic reinforcement. In addition to subjective pain ratings, pain sensitivity was implicitly measured by a behavioral discrimination task. In accordance with the operant learning task, healthy participants learned enhanced perceptual sensitization and habituation, depending on the experimental condition. Whereas healthy persons learned perceptual changes according the experimental protocol, both patient groups failed to show normal operant perceptual learning: FM patients without IBS demonstrated sensitization learning comparable to that in healthy persons, but unexpectedly these patients learned even more pronounced sensitization in the habituation learning condition, contradicting the experimental protocol; FM patients with IBS demonstrated neither learning of enhanced sensitization nor enhanced habituation; no signs of differential operant learning were observable. Thus, operant perceptual learning was impaired in FM patients; whether learning of both enhanced perceptual sensitization and habituation was impaired depended on the presence of comorbid IBS and could not be explained by other clinical characteristics of the patients such as pain threshold, duration of pain, depressive symptoms, or anxiety. While healthy participants learned sensitization and habituation according to an operant task, FM patients without IBS showed enhanced sensitization and FM with IBS no learning.

The role of dopamine in the perceptual modulation of nociceptive stimuli by monetary wins or losses

Dopamine has been suggested to have direct antinociceptive effects. However, effects on the motivation to endure or to avoid nociceptive stimulation would be more in line with dopamines well‐established role in the motivation to obtain reward. Thus, dopamine might either inhibit or facilitate the perception of nociceptive stimuli to bias an organism towards endurance or avoidance depending on the relative importance of the nociceptive input. To test this hypothesis, we conducted two psychophysical experiments in human volunteers. In Experiment 1, the respective antinociceptive and pro‐nociceptive effects of monetary wins and losses were assessed by administering thermal stimuli (three intensities, within‐subject factor) while participants simultaneously won, lost, or neither won nor lost (neutral condition) money (within‐subject factor) in a wheel‐of‐fortune task. In Experiment 2, we tested the effect of low‐dose sulpiride (a centrally‐acting D2‐receptor antagonist increasing the synaptic availability of dopamine via predominant pre‐synaptic blockade) on the same task as in Experiment 1 using a placebo‐controlled, cross‐over design. Monetary wins decreased and losses enhanced the perception of nociceptive stimuli, which was highly reproducible. Sulpiride augmented perceptual modulation by monetary outcomes. This augmentation was driven by increased effects of monetary losses on the perception of nociceptive stimuli. The perception of nociceptive stimuli in the absence of monetary wins and losses was not affected by sulpiride. Based on these findings, we propose a new role of dopamine in the context of nociception: biasing the organism towards a decision in situations with conflicting motivations, depending on the relative importance of the nociceptive input.

Operant conditioning of enhanced pain sensitivity by heat–pain titration

Abstract Operant conditioning mechanisms have been demonstrated to be important in the development of chronic pain. Most experimental studies have investigated the operant modulation of verbal pain reports with extrinsic reinforcement, such as verbal reinforcement. Whether this reflects actual changes in the subjective experience of the nociceptive stimulus remained unclear. This study replicates and extends our previous demonstration that enhanced pain sensitivity to prolonged heat–pain stimulation could be learned in healthy participants through intrinsic reinforcement (contingent changes in nociceptive input) independent of verbal pain reports. In addition, we examine whether different magnitudes of reinforcement differentially enhance pain sensitivity using an operant heat–pain titration paradigm. It is based on the previously developed non‐verbal behavioral discrimination task for the assessment of sensitization, which uses discriminative down‐ or up‐regulation of stimulus temperatures in response to changes in subjective intensity. In operant heat–pain titration, this discriminative behavior and not verbal pain report was contingently reinforced or punished by acute decreases or increases in heat–pain intensity. The magnitude of reinforcement was varied between three groups: low (N1 = 13), medium (N2 = 11) and high reinforcement (N3 = 12). Continuous reinforcement was applied to acquire and train the operant behavior, followed by partial reinforcement to analyze the underlying learning mechanisms. Results demonstrated that sensitization to prolonged heat–pain stimulation was enhanced by operant learning within 1 h. The extent of sensitization was directly dependent on the received magnitude of reinforcement. Thus, operant learning mechanisms based on intrinsic reinforcement may provide an explanation for the gradual development of sustained hypersensitivity during pain that is becoming chronic.

Dopamine and pain sensitivity: neither sulpiride nor acute phenylalanine and tyrosine depletion have effects on thermal pain sensations in healthy volunteers.

Based on animal studies and some indirect clinical evidence, dopamine has been suggested to have anti-nociceptive effects. Here, we investigated directly the effects of increased and decreased availability of extracellular dopamine on pain perception in healthy volunteers. In Study 1, participants ingested, in separate sessions, a placebo and a low dose of the centrally acting D2-receptor antagonist sulpiride, intended to increase synaptic dopamine via predominant pre-synaptic blockade. No effects were seen on thermal pain thresholds, tolerance, or temporal summation. Study 2 used the acute phenylalanine and tyrosine depletion (APTD) method to transiently decrease dopamine availability. In one session participants ingested a mixture that depletes the dopamine amino acid precursors, phenylalanine and tyrosine. In the other session they ingested a nutritionally balanced control mixture. APTD led to a small mood-lowering response following aversive thermal stimulation, but had no effects on the perception of cold, warm, or pain stimuli. In both studies the experimental manipulation of dopaminergic neurotransmission was successful as indicated by manipulation checks. The results contradict proposals that dopamine has direct anti-nociceptive effects in acute experimental pain. Based on dopamine’s well-known role in reward processing, we hypothesize that also in the context of pain, dopamine acts on stimulus salience and might play a role in the initiation of avoidance behavior rather than having direct antinociceptive effects in acute experimental pain.

Different Brain Circuitries Mediating Controllable and Uncontrollable Pain

Uncontrollable, compared with controllable, painful stimulation can lead to increased pain perception and activation in pain-processing brain regions, but it is currently unknown which brain areas mediate this effect. When pain is controllable, the lateral prefrontal cortex (PFC) seems to inhibit pain processing, although it is unclear how this is achieved. Using fMRI in healthy volunteers, we examined brain activation during controllable and uncontrollable stimulation to answer these questions. In the controllable task, participants self-adjusted temperatures applied to their hand of pain or warm intensities to provoke a constant sensation. In the uncontrollable task, the temperature time courses of the controllable task were replayed (yoked control) and participants rated their sensation continuously. During controllable pain trials, participants significantly downregulated the temperature to keep their sensation constant. Despite receiving the identical nociceptive input, intensity ratings increased during the uncontrollable pain trials. This additional sensitization was mirrored in increased activation of pain-processing regions such as insula, anterior cingulate cortex, and thalamus. Further, increased connectivity between the anterior insula and medial PFC (mPFC) in the uncontrollable and increased negative connectivity between dorsolateral PFC (dlPFC) and insula in the controllable task were observed. This suggests a pain-facilitating role of the mPFC during uncontrollable pain and a pain-inhibiting role of the dlPFC during controllable pain, both exerting their respective effects via the anterior insula. These results elucidate neural mechanisms of context-dependent pain modulation and their relation to subjective perception. SIGNIFICANCE STATEMENT Pain control is of uttermost importance and stimulus controllability is an important way to achieve endogenous pain modulation. Here, we show differential effects of controllability and uncontrollability on pain perception and cerebral pain processing. When pain was controllable, the dorsolateral prefrontal cortex downregulated pain-evoked activation in important pain-processing regions. In contrast, sensitization during uncontrollable pain was mediated by increased connectivity of the medial prefrontal cortex with the anterior insula and other pain-processing regions. These novel insights into cerebral pain modulation by stimulus controllability have the potential to improve treatment approaches in pain patients.

Orbitofrontal cortex mediates pain inhibition by monetary reward.

Abstract Pleasurable stimuli, including reward, inhibit pain, but the level of the neuraxis at which they do so and the cerebral processes involved are unknown. Here, we characterized a brain circuitry mediating pain inhibition by reward. Twenty-four healthy participants underwent functional magnetic resonance imaging while playing a wheel of fortune game with simultaneous thermal pain stimuli and monetary wins or losses. As expected, winning decreased pain perception compared to losing. Inter-individual differences in pain modulation by monetary wins relative to losses correlated with activation in the medial orbitofrontal cortex (mOFC). When pain and reward occured simultaneously, mOFCs functional connectivity changed: the signal time course in the mOFC condition-dependent correlated negatively with the signal time courses in the rostral anterior insula, anterior-dorsal cingulate cortex and primary somatosensory cortex, which might signify moment-to-moment down-regulation of these regions by the mOFC. Monetary wins and losses did not change the magnitude of pain-related activation, including in regions that code perceived pain intensity when nociceptive input varies and/or receive direct nociceptive input. Pain inhibition by reward appears to involve brain regions not typically involved in nociceptive intensity coding but likely mediate changes in the significance and/or value of pain.

Brain substrates of reward processing and the μ-opioid receptor: a pathway into pain?

Abstract The processing of reward and reinforcement learning seems to be important determinants of pain chronicity. However, reward processing is already altered early in life and if this is related to the development of pain symptoms later on is not known. The aim of this study was first to examine whether behavioural and brain-related indicators of reward processing at the age of 14 to 15 years are significant predictors of pain complaints 2 years later, at 16 to 17 years. Second, we investigated the contribution of genetic variations in the opioidergic system, which is linked to the processing of both, reward and pain, to this prediction. We used the monetary incentive delay task to assess reward processing, the Childrens Somatization Inventory as measure of pain complaints and tested the effects of 2 single nucleotide polymorphisms (rs1799971/rs563649) of the human &mgr;-opioid receptor gene. We found a significant prediction of pain complaints by responses in the dorsal striatum during reward feedback, independent of genetic predisposition. The relationship of pain complaints and activation in the periaqueductal gray and ventral striatum depended on the T-allele of rs563649. Carriers of this allele also showed more pain complaints than CC-allele carriers. Therefore, brain responses to reward outcomes and higher sensitivity to pain might be related already early in life and may thus set the course for pain complaints later in life, partly depending on a specific opioidergic genetic predisposition.