UC Irvine UC Irvine Previously Published Works Title Mesolimbic dopamine signaling in acute and chronic pain: implications for motivation, analgesia, and addiction. Permalink https://escholarship.org/uc/item/3jp07274 Journal Pain, 157(6) ISSN 0304-3959 Authors Taylor, Anna MW Becker, Susanne Schweinhardt, Petra et al. Publication Date 2016-06-01 DOI 10.1097/j.pain.0000000000000494 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Topical Review Mesolimbic dopamine signaling in acute and chronic pain: implications for motivation, analgesia, and addiction Anna M.W. Taylora,*, Susanne Beckerb, Petra Schweinhardtc, Catherine Cahilld 1. Introduction both rewarding and punishing stimuli are likely to code motivational 9 The mesolimbic dopamine system comprises neurons in the salience. Neurons coding motivational valence would provide a signal for reward seeking, evaluation, and value learning, in line with ventral tegmental area (VTA) and substantia nigra (SN), projecting to 7,58 the ventral striatum. This system was originally described to current theories on the role of dopamine in reward processing. In mediate pleasure and goal-directed movement associated with contrast, neurons coding motivational salience would provide 70 a signal for detection and prediction of highly important events rewarding stimuli. However, it is now clear that dopamine, independent of valence, pursuant to dopamine’s role in salience although crucial for reward processing, drives not the hedonic 54 experience of reward (“liking”) but rather the instrumental behavior processing. These distinct aspects of dopamine neurotransmis- of reward-driven actions (“wanting”).6 Phasic dopamine acts as an sion might be neuroanatomically separate: dopaminergic neurons incentive salience signal underlying reinforcement learning.57,59 coding motivational valence have been found more commonly in the Moreover, aversive stimuli, such as pain, also stimulate dopamine, ventromedial SN and lateral VTA with projections to nucleus further diminishing the idea of dopamine as a “reward” signal.9,10 accumbens shell, whereas neurons coding motivational salience Recent studies suggest that dopamine neurons in the VTA and SN are more often reported in the dorsolateral SN with projections to the Fig. 1 10,39,41,49 form a heterogeneous population tuned to either (or both) aversive nucleus accumbens core ( ). or rewarding stimuli.3,8,30,39 This review will summarize our current understanding of the role of the mesolimbic dopamine system in 3. Dopamine signaling in pain: antinociception or acute pain and the changes that occur in chronic pain. motivational salience? A common suggestion, based on animal studies focusing on pain 2. Dopamine signaling, reward, and punishment behavior, some clinical data, and genetic associations, is that dopamine is antinociceptive by D2 receptors.24,27,33,52,71 Some Although nociceptive events and their conditioned predictive cues experimental works in humans supports this notion by showing 68 depress activity in most dopaminergic neurons, 5% to 15% of increased affective pain ratings after dietary dopamine depletion65 VTA dopaminergic neurons fire preferentially for aversive stim- and increased conditioned pain modulation with D2-receptor 8,13,30,39,41 30 uli, or for both aversive and rewarding stimuli. These activation.67 However, more often, no effects of dopaminergic neurons are probably responsible for the dopamine release after manipulations on a variety of pain tests have been reported.5,65–67 It 3,53 61,73 aversive stimuli, such as psychosocial stress or pain. seems that ascribing an antinociceptive role to dopamine is too The heterogeneity of dopamine neurons in response to aversive simplistic. Examining under which conditions antinociception is and rewarding stimuli suggests that they serve unique functional mostly observed suggests that the common feature is roles. Cells activated by reward and inhibited by punishment are well a motivational–emotional component of the pain tests. In rodent suited to code motivational valence, whereas neurons activated by studies, tonic pain assays such as the formalin or writhing test reveal more often decreases in pain behavior with D2-receptor activation Sponsorships or competing interests that may be relevant to content are disclosed than brief phasic pain stimuli, such as tail flick, hot plate, or paw at the end of this article. pressure.2 In a study in rats with ongoing postsurgical pain, blocking a Department of Psychiatry & Biobehavioral Sciences, University of California, Los dopamine release prevented conditioned place preference (CPP) b Angeles, CA, USA, Department of Cognitive and Clinical Neuroscience, Central associated with peripheral analgesia, clearly indicating the impor- Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 46 Mannheim, Germany, c Alan Edwards Centre for Research on Pain and Faculty of tanceofdopamineformotivatedbehavior. Similarly, in humans, Dentistry, McGill University, Montreal, Canada, d Department of Anesthesiology and dopaminergic manipulations have only been found to affect the Perioperative Care, University of California, Irvine, CA, USA affective component of pain65 or strong behaviorally relevant stimuli 66 *Corresponding author. Address: Department of Psychiatry & Biobehavioral such as immersion of the hand in ice water. Interestingly, even with Sciences, University of California, 760 Westwood Plaza, Box 77 Los Angeles, CA this stimulus, cold pain tolerance initially decreased with D2-receptor 90095, USA. Tel.: (310) 206-7883; fax: (310) 825-7067. E-mail address: ataylor1@ activation and increased only after 2 hours.66 Moreover, striatal ucla.edu (A. M.W. Taylor). dopamine release positively correlates with the magnitude of PAIN 157 (2016) 1194–1198 perceived pain,61,73 which strongly contradicts direct antinociceptive © 2016 International Association for the Study of Pain. This is an open access article effects of dopamine release. Finally, we reported that increasing distributed under the terms of the Creative Commons Attribution-NonCommercial- NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and synaptic dopamine levels by a pharmacological intervention sharing the work provided it is properly cited. The work cannot be changed in any augmented endogenous pain inhibition induced by reward, and way or used commercially. enhanced endogenous pain facilitation by punishment,5 again http://dx.doi.org/10.1097/j.pain.0000000000000494 opposing a simplistic view of dopamine as an antinociceptive agent. 1194 A.M.W. Taylor et al.·157 (2016) 1194–1198 PAIN® Copyright Ó 2016 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited. June 2016· Volume 157· Number 6 www.painjournalonline.com 1195 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 bun- dle,31,32,51 an effect that can be recovered by pharmacological intervention that increases dopamine levels.40,55 Taken to- gether, 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 Figure 1. The role of mesolimbic dopamine neuron subpopulations in of opioids for the treatment of chronic pain has been the growing motivated behavior. Dopamine neurons in the dorsolateral substantia nigra concern of the risk of iatrogenic addiction in this population.1 (SN) project to the nucleus accumbens (NAc) core and encode motivational Given the association of dopamine signaling with addiction salience (stimulus awareness). Dopamine neurons in the ventromedial SN and lateral ventral tegmental area (VTA) project to the NAc shell and encode behaviors, it is possible that the chronic pain–induced disruptions motivational valence (whether the stimulus is positive or negative in value). 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 When these results are considered as a whole, we posit that dopamine system in chronic pain models. dopamine modulates the salience of pain stimuli and thereby On a mechanistic level, opioids