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 stress3,53 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
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 depletion65 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 pain65 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 binding22,23,36,73 and presynaptic dopamine activity26,72 in the striatum at rest and after an acute pain stimulus. In animal studies, chronic pain results in decreased c-Fos activation in the VTA42 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.
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.
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 divisive4,14 (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.
. Alam A, Juurlink DN. The prescription opioid epidemic: an overview for anesthesiologists. Can J Anaesth 2015;63:61–8.
. Altier N, Stewart J. The role of dopamine in the nucleus accumbens in analgesia. Life Sci 1999;65:2269–87.
. Anstrom KK, Miczek KA, Budygin EA. Increased phasic dopamine signaling in the mesolimbic pathway during social defeat in rats. Neuroscience 2009;161:3–12.
. Ballantyne JC, LaForge KS. Opioid dependence and addiction during opioid treatment of chronic pain. PAIN 2007;129:235–55.
. Becker S, Gandhi W, Elfassy NM, Schweinhardt P. The role of dopamine in the perceptual modulation of nociceptive stimuli by monetary wins or losses. Eur J Neurosci 2013;38:3080–8.
. Berridge Kent C, Kringelbach Morten L. Pleasure Systems in the Brain. Neuron 2015;86:646–64.
. Berridge KC, Robinson TE, Aldridge JW. Dissecting components of reward: “liking”, “wanting”, and learning. Curr Opin Pharmacol 2009;9:65–73.
. Brischoux F, Chakraborty S, Brierley DI, Ungless MA. Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli. Proc Natl Acad Sci U S A 2009;106:4894–9.
. Bromberg-Martin ES, Matsumoto M, Hikosaka O. Dopamine in motivational control: rewarding, aversive, and alerting. Neuron 2010;68:815–34.
. Brooks AM, Berns GS. Aversive stimuli and loss in the mesocorticolimbic dopamine system. Trends Cogn Sci 2013;17:281–6.
. Cahill CM, Xue L, Grenier P, Magnussen C, Lecour S, Olmstead MC. Changes in morphine reward in a model of neuropathic pain. Behav Pharmacol 2013;24:207–13.
. Chang PC, Pollema-Mays SL, Centeno MV, Procissi D, Contini M, Baria AT, Martina M, Apkarian AV. Role of nucleus accumbens in neuropathic pain: linked multi-scale evidence in the rat transitioning to neuropathic pain. PAIN 2014;155:1128–39.
. Cohen JY, Haesler S, Vong L, Lowell BB, Uchida N. Neuron-type-specific signals for reward and punishment in the ventral tegmental area. Nature 2012;482:85–8.
. Edlund MJ, Steffick D, Hudson T, Harris KM, Sullivan M. Risk factors for clinically recognized opioid abuse and dependence among veterans using opioids for chronic non-cancer pain. PAIN 2007;129:355–62.
. Elvemo NA, Landro NI, Borchgrevink PC, Haberg AK. Reward responsiveness in patients with chronic pain. Eur J Pain 2015;19:1537–43.
. Ewan E, Martin TJ. Opioid Facilitation of Rewarding Electrical Brain Stimulation Is Suppressed in Rats with Neuropathic Pain. Anesthesiology 2011;114:624–32.
. Fields H. State-dependent opioid control of pain. Nat Rev Neurosci 2004;5:565–75.
. Fields HL. The doctor's dilemma: opiate analgesics and chronic pain. Neuron 2011;69:591–4.
. Fields HL, Margolis EB. Understanding opioid reward. Trends Neurosci 2015;38:217–25.
. Finan PH, Smith MT. The comorbidity of insomnia, chronic pain, and depression: dopamine as a putative mechanism. Sleep Med Rev 2013;17:173–83.
. Georges F, Le Moine C, Aston-Jones G. No effect of morphine on ventral tegmental dopamine neurons during withdrawal. J Neurosci 2006;26:5720–6.
. Hagelberg N, Forssell H, Aalto S, Rinne JO, Scheinin H, Taiminen T, Någren K, Eskola O, Jääskeläinen SK. Altered dopamine D2 receptor binding in atypical facial pain. PAIN 2003;106:43–8.
. Hagelberg N, Forssell H, Rinne JO, Scheinin H, Taiminen T, Aalto S, Luutonen S, Någren K, Jääskeläinen S. Striatal dopamine D1 and D2 receptors in burning mouth syndrome. PAIN 2003;101:149–54.
. Hagelberg N, Jaaskelainen SK, Martikainen IK, Mansikka H, Forssell H, Scheinin H, Hietala J, Pertovaara A. Striatal dopamine D2 receptors in modulation of pain in humans: a review. Eur J Pharmacol 2004;500:187–92.
. Hipolito L, Wilson-Poe A, Campos-Jurado Y, Zhong E, Gonzalez-Romero J, Virag L, Whittington R, Comer SD, Carlton SM, Walker BM, Bruchas MR, Moron JA. Inflammatory Pain Promotes Increased Opioid Self-Administration: role of Dysregulated Ventral Tegmental Area mu Opioid Receptors. J Neurosci 2015;35:12217–31.
. Jaaskelainen SK, Rinne JO, Forssell H, Tenovuo O, Kaasinen V, Sonninen P, Bergman J. Role of the dopaminergic system in chronic pain—a fluorodopa-PET study. PAIN 2001;90:257–60.
. Jarcho JM, Mayer EA, Jiang ZK, Feier NA, London ED. Pain, affective symptoms, and cognitive deficits in patients with cerebral dopamine dysfunction. PAIN 2012;153:744–54.
. King T, Vera-Portocarrero L, Gutierrez T, Vanderah TW, Dussor G, Lai J, Fields HL, Porreca F. Unmasking the tonic-aversive state in neuropathic pain. Nat Neurosci 2009;12:1364–6.
. Koob GF, Le Moal M. Review. Neurobiological mechanisms for opponent motivational processes in addiction. Philos Trans R Soc Lond B Biol Sci 2008;363:3113–23.
. Lammel S, Ion DI, Roeper J, Malenka RC. Projection-specific modulation of dopamine neuron synapses by aversive and rewarding stimuli. Neuron 2011;70:855–62.
. Leitl MD, Onvani S, Bowers MS, Cheng K, Rice KC, Carlezon WA Jr, Banks ML, Negus SS. Pain-related depression of the mesolimbic dopamine system in rats: expression, blockade by analgesics, and role of endogenous kappa-opioids. Neuropsychopharmacology 2014;39:614–24.
. Leitl MD, Potter DN, Cheng K, Rice KC, Carlezon WA Jr, Negus SS. Sustained pain-related depression of behavior: effects of intraplantar formalin and complete freund's adjuvant on intracranial self-stimulation (ICSS) and endogenous kappa opioid biomarkers in rats. Mol Pain 2014;10:62.
. Leknes S, Tracey I. A common neurobiology for pain and pleasure. Nat Rev Neurosci 2008;9:314–20.
. Loggia ML, Berna C, Kim J, Cahalan CM, Gollub RL, Wasan AD, Harris RE, Edwards RR, Napadow V. Disrupted brain circuitry for pain-related reward/punishment in fibromyalgia. Arthritis Rheumatol 2014;66:203–12.
. Lyness WH, Smith FL, Heavner JE, Iacono CU, Garvin RD. Morphine self-administration in the rat during adjuvant-induced arthritis. Life Sci 1989;45:2217–24.
. Martikainen IK, Nuechterlein EB, Pecina M, Love TM, Cummiford CM, Green CR, Stohler CS, Zubieta JK. Chronic Back Pain Is Associated with Alterations in Dopamine Neurotransmission in the Ventral Striatum. J Neurosci 2015;35:9957–65.
. Martin TJ, Kim SA, Buechler NL, Porreca F, Eisenach JC. Opioid self-administration in the nerve-injured rat: relevance of antiallodynic effects to drug consumption and effects of intrathecal analgesics. Anesthesiology 2007;106:312–22.
. Martin TJ, Kim SA, Eisenach JC. Clonidine maintains intrathecal self-administration in rats following spinal nerve ligation. PAIN 2006;125:257–63.
. Matsumoto M, Hikosaka O. Two types of dopamine neuron distinctly convey positive and negative motivational signals. Nature 2009;459:837–41.
. Miller LL, Leitl MD, Banks ML, Blough BE, Negus SS. Effects of the triple monoamine uptake inhibitor amitifadine on pain-related depression of behavior and mesolimbic dopamine release in rats. PAIN 2015;156:175–84.
. Mirenowicz J, Schultz W. Preferential activation of midbrain dopamine neurons by appetitive rather than aversive stimuli. Nature 1996;379:449–51.
. Narita M, Ozaki S, Narita M, Ise Y, Yajima Y, Suzuki T. Change in the expression of c-fos in the rat brain following sciatic nerve ligation. Neurosci Lett 2003;352:231–3.
. Narita M, Kishimoto Y, Ise Y, Yajima Y, Misawa K, Suzuki T. Direct evidence for the involvement of the mesolimbic kappa-opioid system in the morphine-induced rewarding effect under an inflammatory pain-like state. Neuropsychopharmacology 2005;30:111–18.
. Narita M, Suzuki M, Imai S, Narita M, Ozaki S, Kishimoto Y, Oe K, Yajima Y, Yamazaki M, Suzuki T. Molecular mechanism of changes in the morphine-induced pharmacological actions under chronic pain-like state: suppression of dopaminergic transmission in the brain. Life Sci 2004;74:2655–73.
. Navratilova E, Xie JY, Meske D, Qu C, Morimura K, Okun A, Arakawa N, Ossipov M, Fields HL, Porreca F. Endogenous opioid activity in the anterior cingulate cortex is required for relief of pain. J Neurosci 2015;35:7264–71.
. Navratilova E, Xie JY, Okun A, Qu C, Eyde N, Ci S, Ossipov MH, King T, Fields HL, Porreca F. Pain relief produces negative reinforcement through activation of mesolimbic reward-valuation circuitry. Proc Natl Acad Sci U S A 2012;109:20709–13.
. Niikura K, Narita M, Narita M, Nakamura A, Okutsu D, Ozeki A, Kurahashi K, Kobayashi Y, Suzuki M, Suzuki T. Direct evidence for the involvement of endogenous beta-endorphin in the suppression of the morphine-induced rewarding effect under a neuropathic pain-like state. Neurosci Lett 2008;435:257–62.
. Niikura K, Narita M, Okutsu D, Tsurukawa Y, Nanjo K, Kurahashi K, Kobayashi Y, Suzuki T. Implication of endogenous beta-endorphin in the inhibition of the morphine-induced rewarding effect by the direct activation of spinal protein kinase C in mice. Neurosci Lett 2008;433:54–8.
. Nomoto K, Schultz W, Watanabe T, Sakagami M. Temporally extended dopamine responses to perceptually demanding reward-predictive stimuli. J Neurosci 2010;30:10692–702.
. Ozaki S, Narita M, Narita M, Iino M, Sugita J, Matsumura Y, Suzuki T. Suppression of the morphine-induced rewarding effect in the rat with neuropathic pain: implication of the reduction in mu-opioid receptor functions in the ventral tegmental area. J Neurochem 2002;82:1192–8.
. Pereira Do Carmo G, Stevenson GW, Carlezon WA, Negus SS. Effects of pain- and analgesia-related manipulations on intracranial self-stimulation in rats: further studies on pain-depressed behavior. PAIN 2009;144:170–7.
. Potvin S, Grignon S, Marchand S. Human evidence of a supra-spinal modulating role of dopamine on pain perception. Synapse 2009;63:390–402.
. Pruessner JC, Champagne F, Meaney MJ, Dagher A. Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: a positron emission tomography study using [11C]raclopride. J Neurosci 2004;24:2825–31.
. Redgrave P, Gurney K. The short-latency dopamine signal: a role in discovering novel actions? Nat Rev Neurosci 2006;7:967–75.
. Rosenberg MB, Carroll FI, Negus SS. Effects of monoamine reuptake inhibitors in assays of acute pain-stimulated and pain-depressed behavior in rats. J Pain 2013;14:246–59.
. Sagheddu C, Aroni S, De Felice M, Lecca S, Luchicchi A, Melis M, Muntoni AL, Romano R, Palazzo E, Guida F, Maione S, Pistis M. Enhanced serotonin and mesolimbic dopamine transmissions in a rat model of neuropathic pain. Neuropharmacology 2015;97:383–93.
. Salamone JD, Correa M. The mysterious motivational functions of mesolimbic dopamine. Neuron 2012;76:470–85.
. Schultz W. Behavioral dopamine signals. Trends Neurosci 2007;30:203–10.
. Schultz W. Updating dopamine reward signals. Curr Opin Neurobiol 2013;23:229–38.
. Schwartz N, Temkin P, Jurado S, Lim BK, Heifets BD, Polepalli JS, Malenka RC. Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens. Science 2014;345:535–42.
. Scott DJ, Heitzeg MM, Koeppe RA, Stohler CS, Zubieta JK. Variations in the human pain stress experience mediated by ventral and dorsal basal ganglia dopamine activity. J Neurosci 2006;26:10789–95.
. Taylor AM, Castonguay A, Ghogha A, Vayssiere P, Pradhan AA, Xue L, Mehrabani S, Wu J, Levitt P, Olmstead MC, De Koninck Y, Evans CJ, Cahill CM. Neuroimmune Regulation of GABAergic Neurons Within the Ventral Tegmental Area During Withdrawal from Chronic Morphine. Neuropsychopharmacology 2015. in press.
. Taylor AM, Castonguay A, Taylor AJ, Murphy NP, Ghogha A, Cook C, Xue L, Olmstead MC, De Koninck Y, Evans CJ, Cahill CM. Microglia disrupt mesolimbic reward circuitry in chronic pain. J Neurosci 2015;35:8442–50.
. Taylor AMW, Murphy NP, Evans CJ, Cahill CM. Correlation Between Ventral Striatal Catecholamine Content and Nociceptive Thresholds in Neuropathic Mice. J Pain 2014;15:878–85.
. Tiemann L, Heitmann H, Schulz E, Baumkotter J, Ploner M. Dopamine precursor depletion influences pain affect rather than pain sensation. PLoS One 2014;9:1–8.
. Treister R, Pud D, Ebstein RP, Eisenberg E. Dopamine transporter genotype dependent effects of apomorphine on cold pain tolerance in healthy volunteers. PLoS One 2013;8:e63808.
. Treister R, Pud D, Eisenberg E. The dopamine agonist apomorphine enhances conditioned pain modulation in healthy humans. Neurosci Lett 2013;548:115–19.
. Ungless MA, Magill PJ, Bolam JP. Uniform inhibition of dopamine neurons in the ventral tegmental area by aversive stimuli. Science 2004;303:2040–2.
. Wade CL, Krumenacher P, Kitto KF, Peterson CD, Wilcox GL, Fairbanks CA. Effect of chronic pain on fentanyl self-administration in mice. PLoS One 2013;8:E79239.
. Wise RA. The dopamine synapse and the notion of “pleasure centers” in the brain. Trends Neurosci 1980;3:91–5.
. Wood PB. Role of central dopamine in pain and analgesia. Expert Rev Neurother 2008;8:781–97.
. Wood PB, Patterson JC II, Sunderland JJ, Tainter KH, Glabus MF, Lilien DL. Reduced presynaptic dopamine activity in fibromyalgia syndrome demonstrated with positron emission tomography: a pilot study. J Pain 2007;8:51–8.
. Wood PB, Schweinhardt P, Jaeger E, Dagher A, Hakyemez H, Rabiner EA, Bushnell MC, Chizh BA. Fibromyalgia patients show an abnormal dopamine response to pain. Eur J Neurosci 2007;25:3576–82.
. Wu Y, Na X, Zang Y, Cui Y, Xin W, Pang R, Zhou L, Wei X, Li Y, Liu X. Upregulation of tumor necrosis factor-alpha in nucleus accumbens attenuates morphine-induced rewarding in a neuropathic pain model. Biochem Biophys Res Commun 2014;449:502–7.
. Xie JY, Qu C, Patwardhan A, Ossipov MH, Navratilova E, Becerra L, Borsook D, Porreca F. Activation of mesocorticolimbic reward circuits for assessment of relief of ongoing pain: a potential biomarker of efficacy. PAIN 2014;155:1659–66.
. Zhang Y, Picetti R, Butelman ER, Schlussman SD, Ho A, Kreek MJ. Behavioral and neurochemical changes induced by oxycodone differ between adolescent and adult mice. Neuropsychopharmacology 2009;34:912–22.
. Zhang Z, Tao W, Hou YY, Wang W, Lu YG, Pan ZZ. Persistent pain facilitates response to morphine reward by downregulation of central amygdala GABAergic function. Neuropsychopharmacology 2014;39:2263–71.