Doubling your payoff: winning pain relief engages endogenous pain inhibition

When in pain, pain relief is much sought after, particularly for individuals with chronic pain. In analogy to augmentation of the hedonic experience (“liking”) of a reward by the motivation to obtain a reward (“wanting”), the seeking of pain relief in a motivated state might increase the experience of pain relief when obtained. We tested this hypothesis in a psychophysical experiment in healthy human subjects, by assessing potential pain-inhibitory effects of pain relief “won” in a wheel of fortune game compared with pain relief without winning, exploiting the fact that the mere chance of winning induces a motivated state. The results show pain-inhibitory effects of pain relief obtained by winning in behaviorally assessed pain perception and ratings of pain intensity. Further, the higher participants scored on the personality trait novelty seeking, the more pain inhibition was induced. These results provide evidence that pain relief, when obtained in a motivated state, engages endogenous pain-inhibitory systems beyond the pain reduction that underlies the relief in the first place. Consequently, such pain relief might be used to improve behavioral pain therapy, inducing a positive, perhaps self-amplifying feedback loop of reduced pain and improved functionality

Functional connectivity of the amygdala is linked to individual differences in emotional pain facilitation

The amygdala is central to emotional processing of sensory stimuli, including pain. Because recent findings suggest that individual differences in emotional processes play a part in the development of chronic pain, a better understanding of the individual patterns of functional connectivity that makes individuals susceptible to emotionally modulated facilitation of pain is needed. We therefore investigated the neural correlates of individual differences in emotional pain facilitation using resting-state functional magnetic resonance imaging (rs-fMRI) with an amygdala seed. Thirty-seven participants took part in 3 separate sessions, during which pain sensitivity was tested (session 1), participants underwent rs-fMRI (session 2), and emotional pain modulation was assessed (session 3). The amygdala served as seed for the rs-fMRI analysis, and whole-brain voxel-wise connectivity was tested. Pain modulatory scores were entered as regressor for the group analysis. Stronger connectivity of the amygdala to S1/M1, S2/operculum, and posterior parietal cortex at rest characterized individuals who showed greater pain facilitation by negative emotions. When comparing the amygdala networks associated with pain unpleasantness and with pain-intensity modulation, most of the identified areas were equally related to either pain rating type; only amygdala connectivity to S1/M1 was found to predict pain-intensity modulation specifically. We demonstrate that trait-like patterns of functional connectivity between amygdala and cortical regions involved in sensory and motor responses are associated with the individual amplitude of pain facilitation by negative emotional states. Our results are an early step toward improved understanding of the mechanisms that give rise to individual differences in emotional pain modulation

Multicenter assessment of quantitative sensory testing (QST) for the detection of neuropathic-like pain responses using the topical capsaicin model

Background: The use of quantitative sensory testing (QST) in multicenter studies has been quite limited, due in part to lack of standardized procedures among centers. Aim: The aim of this study was to assess the application of the capsaicin pain model as a surrogate experimental human model of neuropathic pain in different centers and verify the variation in reports of QST measures across centers. Methods: A multicenter study conducted by the Quebec Pain Research Network in six laboratories allowed the evaluation of nine QST parameters in 60 healthy subjects treated with topical capsaicin to model unilateral pain and allodynia. The same measurements (without capsaicin) were taken in 20 patients with chronic neuropathic pain recruited from an independent pain clinic. Results: Results revealed that six parameters detected a significant difference between the capsaicin-treated and the control skin areas: (1) cold detection threshold (CDT) and (2) cold pain threshold (CPT) are lower on the capsaicin-treated side, indicating a decreased in cold sensitivity; (3) heat pain threshold (HPT) was lower on the capsaicin-treated side in healthy subjects, suggesting an increased heat pain sensitivity; (4) dynamic mechanical allodynia (DMA); (5) mechanical pain after two stimulations (MPS2); and (6) mechanical pain summation after ten stimulations (MPS10), are increased on the capsaicin-treated side, suggesting an increased in mechanical pain (P < 0.002). CDT, CPT and HPT showed comparable effects across all six centers, with CPT and HPT demonstrating the best sensitivity. Data from the patients showed significant difference between affected and unaffected body side but only with CDT. Conclusion: These results provide further support for the application of QST in multicenter studies examining normal and pathological pain responses

Do “central sensitization” questionnaires reflect measures of nociceptive sensitization or psychological constructs? Protocol for a systematic review

Introduction: Central sensitization (CS) was first defined in animal studies to be increased nociceptive responsiveness due to sensitization of neurons in the central nervous system, usually the result of prolonged nociceptive input or a disease state. Recently, the concept of CS has been adopted in clinical assessments of chronic pain, but its diagnosis in humans has expanded to include the enhancement of a wide range of nociceptive, sensory, and emotional responses. Many poorly understood pain disorders are referred to as “central sensitivity syndrome,” a term associated with a broad range of hypervigilant sensory and emotional responses. Diagnosis often involves a review of medical records and an assessment of behaviour, emotional disposition, and overall sensitivity of a patient. Obviously, these assessments are unable to directly capture the responsiveness of nociceptive neurons. The purpose of this review is to ascertain whether self-report questionnaires associated with central sensitization and the diagnosis of central sensitivity syndrome are associated with enhanced nociceptive responses or whether they more validly measure sensitivity in a broader sense (ie, including emotional responses). Methods: Following the PRISMA guidelines, a detailed search of studies that involve the Central Sensitization Inventory or Pain Sensitivity Questionnaire correlated with either nociceptive sensory tests (quantitative sensory testing) or emotional hypervigilance (anxiety, depression, stress, etc) will be conducted on MEDLINE, PsychINFO, and Web of Science. Perspective: The review is expected to synthesize correlations between sensitivity questionnaires and nociceptive or emotional sensitivity to determine whether these questionnaires reflect a broadened understanding of the term “central sensitization.

Endogenous opioids contribute to the feeling of pain relief in humans

Endogenous opioids mediate the pleasurable responses to positively reinforcing stimuli such as palatable food. Yet, the reduction or omission of a negative experience can also be rewarding (negative reinforcement). As such, pain relief leads to negative reinforcement and evokes a pleasant feeling in humans. Although it has been shown that the feeling of pleasure associated with positive reinforcement is at least partly mediated through endogenous opioids, it is currently unknown whether similar neurochemical mechanisms are involved in the pleasant feeling evoked by pain relief. In this study, 27 healthy participants completed 2 identical experimental sessions, 1 with placebo and 1 with naltrexone, an endogenous opioid antagonist. Pain relief was induced by superficial cooling after heat stimulation of capsaicin-sensitized skin. Participants rated the relief and pleasantness in response to the cooling. Endogenous opioid blockade by naltrexone decreased relief and pleasantness ratings compared with placebo (P 5 0.0027). This study provides evidence that endogenous opioids play a role in mediating the pleasant feeling of pain relief in humans. Clinically, the rewarding nature of pain relief and its underlying mechanisms require consideration because of their potential reinforcing effects on behaviors that might be beneficial short-term but maladaptive long-term

Orbitofrontal cortex mediates pain inhibition by monetary reward

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 momentto-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

The influence of pain on reward processing

Avoiding pain and seeking reward are motivational states crucial for survival. When activated simultaneously, they are likely to interact (Becker et al., 2012; Navratilova and Porreca 2014). Chronic pain, for example, has been associated with anhedonia, the inability to feel pleasure (Marbach and Lund 1981; Marbach et al., 1983). However, these studies did not control for depression, a common co-morbidity of chronic pain. Thus it remains unknown how pain per se changes reward processing in humans. Addressing this question, evidence from a rodent study suggests an increased motivation to obtain food reward in acutely injured rats (Low and Fitzgerald 2012). No data in humans exist, however, to confirm this interaction of pain and reward. Therefore, the first aim of this thesis was to investigate the influence of acute pain in healthy people on motivational and hedonic aspects of reward processing. Using a monetary reward task we showed that acute pain increased the motivation to obtain reward while hedonic ('liking') ratings were unaffected by pain. The increase in motivation was correlated to perceived pain unpleasantness. Therefore, we concluded that people with acute pain try to compensate for the unpleasant state their pain provokes by obtaining higher wins. This mechanism implies an adaptive, active coping mechanism in a situation where pain itself cannot be avoided.After I had investigated the influence of acute pain on positive rewards, I was next interested in the effect of pain on the avoidance of negative states (i.e. pain). Using a pain-avoidance task we could show that a painful stimulus which participants had unsuccessfully tried to avoid, led (i) to decreased expectations to be able to avoid the next painful stimulus, and (ii) to decreased pain avoidance behavior. We conclude that characteristics of helplessness (Abramson et al., 1978) can be induced within our experimental setting.Further, we sought to characterize the neural underpinnings of the pain-induced reduction in the motivation to avoid pain. Using functional magnetic resonance imaging (fMRI), we engaged healthy participants in a similar pain avoidance task. We replicated our previous finding: an unsuccessful avoidance attempt reduced the motivation to avoid pain. The pain-induced reduction in motivation was predicted by a decrease in periaqueductal grey (PAG) activation, highlighting a key role of the PAG and its network in human pain avoidance behavior. Based on the concept of learned helplessness we hypothesized that the observed influence of pain on pain avoidance should be amplified in patients with a history of unavoidable pain. Therefore, we performed the same fMRI experiment in a group of migraineurs. We found that migraineurs were, indeed, more affected by previous pain in their avoidance behavior. Similar to healthy controls, the decrease in pain avoidance following pain was explained by a pain-induced reduction in PAG activation; these changes of the PAG correlated positively with self-reported helplessness in migraineurs. These studies improve our understanding of the interplay between pain and reward; they highlight the role of reward processing in coping with pain and suggest PAG as a central structure underlying these coping mechanisms. In this context, a vicious circle will be proposed demonstrating how helplessness relates to altered PAG activity and, ultimately, worsens clinical measures in migraineurs. Interrupting this circle may provide promising avenues to reduce suffering and promote well-being in pain patients.Éviter la douleur et rechercher les récompenses sont des états émotionnels essentiels à la survie. Quand ils sont activés simultanément, ils sont susceptibles d'interagir. La douleur chronique, par exemple, a été associée dans certaines études à l'anhédonie. Cependant, ces études ne mesuraient pas la dépression, une comorbidité courante de la douleur chronique. On ne sait donc pas comment la douleur proprement dite modifie le traitement de la récompense chez l'être humain. Tentant de répondre à cette question, des données probantes provenant d'une étude réalisée à l'aide de rongeurs suggèrent une motivation accrue d'obtenir une récompense alimentaire chez les rats gravement blessés. Aucune donnée n'existe chez les humains, cependant, pour confirmer cette interaction. À l'aide d'une tâche récompensée financièrement, nous avons montré que la douleur aigue accroissait la motivation à obtenir une récompense, alors que les taux hédoniques (le fait d'apprécier quelque chose) n'étaient pas influencés par la douleur. L'accroissement de la motivation a été associé au caractère désagréable perçu de la douleur. Par conséquent, nous avons conclu que les personnes souffrant de douleur aigue tentaient de compenser pour l'état désagréable que provoquait leur douleur en obtenant des gains plus élevés. Ce mécanisme sous-entend un mécanisme compensatoire actif et adaptatif dans une situation où la douleur elle-même ne peut être évitée. Après que j'aie étudié l'influence de la douleur aigue sur les récompenses positives, je me suis ensuite penchée sur l'effet de la douleur sur l'évitement d'états négatifs (c.-à-d. la douleur). À l'aide d'une tâche visant à éviter la douleur, nous pouvions montrer qu'un stimulus douloureux que les participants avaient essayé, sans succès, d'éviter a mené (i) à une diminution des attentes quant aux capacités d'éviter le prochain stimulus douloureux et (ii) à une diminution du comportement de l'évitement de la douleur. De plus, nous avons cherché à caractériser les fondements neuraux de la réduction induite par la douleur de la motivation à éviter cette douleur. À l'aide de l'IRMf, nous avons fait participer des sujets sains à une tâche semblable d'évitement de la douleur. Une tentative non réussie d'éviter la douleur a réduit la motivation à éviter la douleur. La réduction induite par la douleur de cette motivation était prédite par une diminution de l'activation de la substance grise périaqueducale (SGP), mettant en évidence un rôle clé de la SGP et de son réseau dans le comportement de l'évitement de la douleur chez l'être humain. En nous fondant sur le concept d'impuissance acquise, nous avons émis l'hypothèse que l'influence observée de la douleur sur l'évitement de la douleur devrait être amplifiée chez les patients ayant des antécédents de douleur inévitable. Par conséquent, nous avons effectuée la même expérience d'IRMf auprès d'un groupe de personnes souffrant de migraines. Nous avons découvert que le comportement d'évitement de ces personnes était, effectivement, davantage influencé par la douleur précédente. La diminution de l'évitement de la douleur à la suite de celle-ci s'expliquait par une réduction induite par la douleur de l'activation de la SGP; ces modifications de la SGP étaient positivement associées à l'impuissance autodéclarée chez les migraineurs. Ces études améliorent notre compréhension du lien entre douleur et récompense; elles mettent en relief le rôle du traitement de la récompense pour faire face à la douleur et laissent entendre que la SGP est une structure centrale sous-jacente à ces mécanismes de compensation. Dans ce contexte, un cercle vicieux démontrant comment l'impuissance est associée à l'activité modifiée de la SGP sera proposé et, ultimement, comment cette impuissance nuit aux mesures cliniques chez les migraineurs. L'interruption de ce cercle peut fournir des avenues prometteuses pour réduire la souffrance et promouvoir le bien-être chez les patients atteints de douleurs

Reward processing as a common diathesis for chronic pain and depression

Pain disorders and psychiatric illness are strongly comorbid, particularly in the context of Major Depressive Disorder (MDD). While these disorders account for a significant amount of global disability, the mechanisms of their overlap remain unclear. Understanding these mechanisms is of vital importance to developing prevention strategies and interventions that target both disorders. Of note, brain reward processing may be relevant to explaining how the comorbidity arises, given pain disorders and MDD can result in maladaptive reward responsivity that limits reward learning, appetitive approach behaviours and consummatory response. In this review, we discuss this research and explore the possibility of reward processing deficits as a common diathesis to explain the manifestation of pain disorders and MDD. Specifically, we hypothesize that contextual physical or psychological events (e.g. surgery, divorce) in the presence of a reward impairment diathesis worsens symptoms and results in a negative feedback loop that increases the chronicity and probability of developing the other disorder. We also highlight the implications for treatment and provide a framework for future research

Conditioned Pain Modulation (CPM) is associated with heightened connectivity between the periaqueductal grey (PAG) and cortical regions

Introduction Conditioned Pain Modulation (CPM) is a psychophysical assessment used to estimate the efficiency of an individual’s endogenous modulatory mechanisms. CPM has been used as a predictive assessment for the development of chronic pain and responses to pain interventions. While much is known about the spinal cord mechanisms associated with CPM, less is known about the contribution of supraspinal and especially cortical regions. Objectives We aimed to explore how whole-brain connectivity of a core modulatory region, the periaqueductal grey (PAG), is associated with conditioned pain modulation, and endogenous pain modulation more broadly Methods We measured CPM and resting-state connectivity of 40 healthy volunteers, absent of chronic pain diagnoses. As a region of interest, we targeted the PAG, which is directly involved in endogenous modulation of input to the spinal cord and is a key node within the descending pain modulation network. Results We found that CPM was associated with heightened connectivity between the PAG and key regions associated with pain processing and inhibition, such as the primary & secondary somatosensory cortices, as well as the motor, premotor and dorsolateral prefrontal cortices. These findings are consistent with connectivity findings in other resting-state and event-related fMRI studies. Conclusion These findings indicate that individuals who are efficient modulators have greater functional connectivity between the PAG, and regions involved in processing pain. The heightened connectivity of these regions may contribute to the beneficial outcomes in clinical pain management, as quantified by CPM. These results may function as brain-based biomarkers for vulnerability or resilience to pain. In Brief Conditioned Pain Modulation is associated with heightened connectivity between a key pain modulatory region, the periaqueductal gray, and regions associated with processing pain