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

      a , * , b , c , d


      Wolters Kluwer

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          1. Introduction 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. 2. Dopamine signaling, reward, and punishment Although nociceptive events and their conditioned predictive cues depress activity in most dopaminergic neurons, 68 5% to 15% of VTA dopaminergic neurons fire preferentially for aversive stimuli, 8,13,30,39,41 or for both aversive and rewarding stimuli. 30 These neurons are probably responsible for the dopamine release after aversive stimuli, such as psychosocial stress 3,53 or pain. 61,73 The heterogeneity of dopamine neurons in response to aversive and rewarding stimuli suggests that they serve unique functional roles. Cells activated by reward and inhibited by punishment are well suited to code motivational valence, whereas neurons activated by both rewarding and punishing stimuli are likely to code motivational salience. 9 Neurons coding motivational valence would provide a signal for reward seeking, evaluation, and value learning, in line with current theories on the role of dopamine in reward processing. 7,58 In contrast, neurons coding motivational salience would provide a signal for detection and prediction of highly important events independent of valence, pursuant to dopamine's role in salience processing. 54 These distinct aspects of dopamine neurotransmission might be neuroanatomically separate: dopaminergic neurons coding motivational valence have been found more commonly in the ventromedial SN and lateral VTA with projections to nucleus accumbens shell, whereas neurons coding motivational salience are more often reported in the dorsolateral SN with projections to the nucleus accumbens core (Fig. 1). 10,39,41,49 Figure 1 The role of mesolimbic dopamine neuron subpopulations in motivated behavior. Dopamine neurons in the dorsolateral substantia nigra (SN) project to the nucleus accumbens (NAc) core and encode motivational salience (stimulus awareness). Dopamine neurons in the ventromedial SN and lateral ventral tegmental area (VTA) project to the NAc shell and encode motivational valence (whether the stimulus is positive or negative in value). 3. Dopamine signaling in pain: antinociception or motivational salience? A common suggestion, based on animal studies focusing on pain behavior, some clinical data, and genetic associations, is that dopamine is antinociceptive by D2 receptors. 24,27,33,52,71 Some experimental works in humans supports this notion by showing increased affective pain ratings after dietary dopamine depletion 65 and increased conditioned pain modulation with D2-receptor activation. 67 However, more often, no effects of dopaminergic manipulations on a variety of pain tests have been reported. 5,65–67 It seems that ascribing an antinociceptive role to dopamine is too simplistic. Examining under which conditions antinociception is mostly observed suggests that the common feature is a motivational–emotional component of the pain tests. In rodent studies, tonic pain assays such as the formalin or writhing test reveal more often decreases in pain behavior with D2-receptor activation than brief phasic pain stimuli, such as tail flick, hot plate, or paw pressure. 2 In a study in rats with ongoing postsurgical pain, blocking dopamine release prevented conditioned place preference (CPP) associated with peripheral analgesia, clearly indicating the importance of dopamine for motivated behavior. 46 Similarly, in humans, dopaminergic manipulations have only been found to affect the affective component of pain 65 or strong behaviorally relevant stimuli such as immersion of the hand in ice water. 66 Interestingly, even with this stimulus, cold pain tolerance initially decreased with D2-receptor activation and increased only after 2 hours. 66 Moreover, striatal dopamine release positively correlates with the magnitude of perceived pain, 61,73 which strongly contradicts direct antinociceptive effects of dopamine release. Finally, we reported that increasing synaptic dopamine levels by a pharmacological intervention augmented endogenous pain inhibition induced by reward, and enhanced endogenous pain facilitation by punishment, 5 again opposing a simplistic view of dopamine as an antinociceptive agent. When these results are considered as a whole, we posit that dopamine modulates the salience of pain stimuli and thereby mediates the motivation to avoid or endure pain depending on the situational context. The observation that mesolimbic dopamine neurons activated by aversive stimuli also respond to appetitive stimuli supports the idea that dopamine codes the motivational salience of pain and may act as a “decision aid” whether pain should be endured to obtain a reward. Thereby, they would subserve an important function of Fields' Motivation-Decision Model of Pain. 17 This framework means that dopamine would play a crucial role in pain avoidance and coping responses, 2 processes that are of high clinical importance. 4. Dopamine dysfunction in chronic pain There is now ample evidence from both the animal and human literature to suggest that chronic pain results in a hypodopaminergic tone that impairs motivated behavior. Human imaging studies have found lowered responsiveness within the mesolimbic dopamine system in response to salient stimuli in patients with chronic pain. 34,36 For example, patients with chronic pain have lower D2-receptor binding 22,23,36,73 and presynaptic dopamine activity 26,72 in the striatum at rest and after an acute pain stimulus. In animal studies, chronic pain results in decreased c-Fos activation in the VTA 42 and decreased overall dopamine levels and striatal D2 receptors. 12,56,64,74 Dopamine signaling is important for motivating approach or avoidance behavior following presentation of a salient stimulus, rather than the hedonic value. In this way, chronic pain results in behavior indicative of a hypodopaminergic state. When food rewards are easily available (ie, under a fixed ratio operant responding task), there is no difference in reward consumption between chronic pain and control groups. 37,69 However, as the energy required to solicit a food reward increases (eg, under a progressive ratio schedule), animals with chronic pain consume significantly less food than controls. 25,60 Thus, we conclude that although the hedonic value of food is unaffected in animals with chronic pain, the drive to obtain these rewards is reduced. Moreover, persistent and chronic pain decreases intracranial self-stimulation of the medial forebrain bundle, 31,32,51 an effect that can be recovered by pharmacological intervention that increases dopamine levels. 40,55 Taken together, these results indicate that chronic pain leads to a significant impairment of mesolimbic dopamine activity that interferes with motivated behavior. 5. Opioid reward and chronic pain The mesolimbic dopamine system drives approach or avoidance behavior following a salient cue, such as acute pain. In conditions of chronic pain, deficits in dopamine signaling emerge that impair motivated behavior. Reinforcing drugs, such as opioids, also stimulate the dopamine system, a function that underscores their highly salient and rewarding attributes. Long-term exposure to opioids disrupts dopamine signaling, 21,62,76 a phenomenon that contributes to the downward shift in the allostatic state associated with addiction. 29 Coincident with the exponential rise of opioids for the treatment of chronic pain has been the growing concern of the risk of iatrogenic addiction in this population. 1 Given the association of dopamine signaling with addiction behaviors, it is possible that the chronic pain–induced disruptions in dopamine signaling may alter the addiction liability of opioids used for pain management. Recent research has begun to address these issues by assessing how opioids interact with the dopamine system in chronic pain models. On a mechanistic level, opioids are less effective at stimulating mesolimbic dopamine neurons in chronic pain. For example, morphine-stimulated GTPϒS (a measure of μ-opioid receptor activation) is significantly reduced in the VTA, 44 and systemic opioids fail to stimulate extracellular dopamine in the striatum in animals with chronic pain. 25,50,63 The deficits in opioid-stimulated dopamine in chronic pain suggest alterations in salience and motivated behavior. However, assessing opioid reward in chronic pain has an added level of complexity, because systemic opioids will engage dopamine signaling and stimulate motivated approach behavior through 2 distinct mechanisms: direct activation of the mesolimbic dopamine neurons and indirectly through analgesic effects mediated by the inhibition of pain pathways throughout the peripheral and central nervous system. Direct inhibition of pain pathways is rewarding in the context of pain, as evidenced by the fact that peripherally or spinally restricted analgesics, such as lidocaine and intrathecal clonidine, stimulate dopamine release, are self-administered, and produce a place preference in animals with pain. 28,37,38,46,75 The rewarding effects of opioid analgesia also involve supraspinal circuits outside the VTA. For example, localized injection of opioids into the anterior cingulate cortex is sufficient to stimulate striatal dopamine and produce a place preference. 45 Therefore, the salience of opioids is context-dependent and may engage different circuits depending on the preexisting behavioral state of the subject. 17,19 The challenge in the chronic pain literature is to tease out these factors when assessing opioid reward in the whole animal. When opioid reward is assessed using self-administration, motivated behavior is reduced only at doses that fail to effectively mitigate pain. 25,35,37,69 In fact, the presence of analgesia is required for opioid reward behavior in chronic pain, given that spinally blocking pain interferes with opioid self-administration and CPP. 35,37,38 Equivocal findings have been reported when opioid reward is assessed with the CPP assay, 11,43–45,48,50,63,77 perhaps because systemic drug administration is engaging circuits outside the midbrain dopamine system. However, when opioids are administered directly into the VTA, they do not produce a place preference, 47,63 and the potentiating effect of opioids on VTA intracranial self-stimulation is diminished in animals with chronic pain. 16 Taken together, we conclude that although the mesolimbic dopamine system is less responsive in chronic pain, systemic opioids remain reinforcing through their analgesic effects. Importantly, analgesia seems to be required for systemic opioids to be reinforcing in chronic pain. 6. Conclusions Our understanding of the mesolimbic dopamine system has evolved significantly over the past decade, and now the integration of this system in the context of acute and chronic pain needs refinement. We no longer equate dopamine release with pleasure or reward but rather acknowledge that dopamine neurons are a heterogeneous population of neurons that respond to both appetitive and aversive stimuli to mediate motivated behavior. Release of dopamine after an acute painful stimulus acts as a salience cue and is critical for approach or avoidance behavior. There are now multiple lines of evidence that show chronic pain leads to a hypodopaminergic state that impairs motivated behavior (Fig. 2). Decreased reward responsivity may underlie a key system mediating the anhedonia and depression common with chronic pain. 15,20,27 Strategies to restore dopamine signaling may represent a novel approach to manage these affective sequelae of chronic pain. Figure 2 The mesolimbic dopamine system is formed of a heterogeneous population of neurons that respond to both appetitive and aversive stimuli and mediate motivated behavior. Release of dopamine after an acute painful stimulus acts as a salience cue, mediating the motivation to avoid or endure pain depending on the situational context. Conversely, relief of pain is normally interpreted as a positive salient stimulus and stimulates the release of dopamine in healthy individuals. Chronic pain, however, results in a hypodopaminergic state that impairs motivated behavior. Decreased reward responsivity may underlie a key system mediating the anhedonia and depression common with chronic pain. The story becomes more nuanced when assessing motivated behavior toward opioids in chronic pain. Research shows that the ability of opioids to stimulate the mesolimbic dopamine system is impaired, and this seems to translate into reduced responsiveness to appetitive stimuli. However, opioids maintain their reinforcement in subjects with chronic pain through their analgesic properties, emphasizing the notion that motivated behavior and reward are context-dependent. A final question asks whether these changes affect opioid addiction liability. Unfortunately, it remains difficult to draw such conclusions from the animal literature, and clinical reports of rates of opioid addiction among the chronic pain population remain divisive 4,14 (for review, see Reference 18). One issue is that chronic pain states are not static, and as the pain condition progresses or resolves so might the function of the dopamine system. This idea is supported by an animal study that found self-administration of low doses of opioids returned to normal as the chronic pain state resolved. 35 This study highlights the fact that the motivational drive for opioids is constantly adapting with the internal states of the subject. Discussing addiction liability in a population with possibly fluctuating pain states is a difficult task requiring a nuanced appreciation of the motivational state in chronic pain. Conflict of interest statement The authors have no conflicts of interest to declare. A.M.W. Taylor was supported by a Postdoctoral Fellowship from the Canadian Institutes of Health Research and The Shirley and Stefan Hatos Foundation. S. Becker was supported by the Olympia Morata Programme of the Heidelberg University. P. Schweinhardt is supported by a Canada Research Chair Tier II. C. Cahill was supported by the Shirley and Stefan Hatos Foundation.

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          Most cited references 75

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          Dopamine in motivational control: rewarding, aversive, and alerting.

          Midbrain dopamine neurons are well known for their strong responses to rewards and their critical role in positive motivation. It has become increasingly clear, however, that dopamine neurons also transmit signals related to salient but nonrewarding experiences such as aversive and alerting events. Here we review recent advances in understanding the reward and nonreward functions of dopamine. Based on this data, we propose that dopamine neurons come in multiple types that are connected with distinct brain networks and have distinct roles in motivational control. Some dopamine neurons encode motivational value, supporting brain networks for seeking, evaluation, and value learning. Others encode motivational salience, supporting brain networks for orienting, cognition, and general motivation. Both types of dopamine neurons are augmented by an alerting signal involved in rapid detection of potentially important sensory cues. We hypothesize that these dopaminergic pathways for value, salience, and alerting cooperate to support adaptive behavior. Copyright © 2010 Elsevier Inc. All rights reserved.
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            Two types of dopamine neuron distinctly convey positive and negative motivational signals.

            Midbrain dopamine neurons are activated by reward or sensory stimuli predicting reward. These excitatory responses increase as the reward value increases. This response property has led to a hypothesis that dopamine neurons encode value-related signals and are inhibited by aversive events. Here we show that this is true only for a subset of dopamine neurons. We recorded the activity of dopamine neurons in monkeys (Macaca mulatta) during a Pavlovian procedure with appetitive and aversive outcomes (liquid rewards and airpuffs directed at the face, respectively). We found that some dopamine neurons were excited by reward-predicting stimuli and inhibited by airpuff-predicting stimuli, as the value hypothesis predicts. However, a greater number of dopamine neurons were excited by both of these stimuli, inconsistent with the hypothesis. Some dopamine neurons were also excited by both rewards and airpuffs themselves, especially when they were unpredictable. Neurons excited by the airpuff-predicting stimuli were located more dorsolaterally in the substantia nigra pars compacta, whereas neurons inhibited by the stimuli were located more ventromedially, some in the ventral tegmental area. A similar anatomical difference was observed for their responses to actual airpuffs. These findings suggest that different groups of dopamine neurons convey motivational signals in distinct manners.
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              Dissecting components of reward: 'liking', 'wanting', and learning.

              In recent years significant progress has been made delineating the psychological components of reward and their underlying neural mechanisms. Here we briefly highlight findings on three dissociable psychological components of reward: 'liking' (hedonic impact), 'wanting' (incentive salience), and learning (predictive associations and cognitions). A better understanding of the components of reward, and their neurobiological substrates, may help in devising improved treatments for disorders of mood and motivation, ranging from depression to eating disorders, drug addiction, and related compulsive pursuits of rewards.

                Author and article information

                Wolters Kluwer (Philadelphia, PA )
                19 January 2016
                June 2016
                : 157
                : 6
                : 1194-1198
                [a ]Department of Psychiatry & Biobehavioral Sciences, University of California, Los Angeles, CA, USA
                [b ]Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
                [c ]Alan Edwards Centre for Research on Pain and Faculty of Dentistry, McGill University, Montreal, Canada
                [d ]Department of Anesthesiology and Perioperative Care, University of California, Irvine, CA, USA
                Author notes
                [* ]Corresponding author. Address: Department of Psychiatry & Biobehavioral Sciences, University of California, 760 Westwood Plaza, Box 77 Los Angeles, CA 90095, USA. Tel.: (310) 206-7883; fax: (310) 825-7067. E-mail address: ataylor1@ (A. M.W. Taylor).
                PAIN-D-14-14218 00004
                © 2016 International Association for the Study of Pain

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.

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