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
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”).
Phasic dopamine acts as an incentive salience signal underlying reinforcement learning.
Moreover, aversive stimuli, such as pain, also stimulate dopamine, further diminishing
the idea of dopamine as a “reward” signal.
Recent studies suggest that dopamine neurons in the VTA and SN form a heterogeneous
population tuned to either (or both) aversive or rewarding stimuli.
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,
5% to 15% of VTA dopaminergic neurons fire preferentially for aversive stimuli,
or for both aversive and rewarding stimuli.
These neurons are probably responsible for the dopamine release after aversive stimuli,
such as psychosocial stress
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.
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
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.
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).
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
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.
Some experimental works in humans supports this notion by showing increased affective
pain ratings after dietary dopamine depletion
and increased conditioned pain modulation with D2-receptor activation.
However, more often, no effects of dopaminergic manipulations on a variety of pain
tests have been reported.
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.
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.
Similarly, in humans, dopaminergic manipulations have only been found to affect the
affective component of pain
or strong behaviorally relevant stimuli such as immersion of the hand in ice water.
Interestingly, even with this stimulus, cold pain tolerance initially decreased with
D2-receptor activation and increased only after 2 hours.
Moreover, striatal dopamine release positively correlates with the magnitude of perceived
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,
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.
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.
For example, patients with chronic pain have lower D2-receptor binding
and presynaptic dopamine activity
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
and decreased overall dopamine levels and striatal D2 receptors.
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.
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.
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,
an effect that can be recovered by pharmacological intervention that increases dopamine
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,
a phenomenon that contributes to the downward shift in the allostatic state associated
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.
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
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,
and systemic opioids fail to stimulate extracellular dopamine in the striatum in animals
with chronic pain.
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.
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.
Therefore, the salience of opioids is context-dependent and may engage different circuits
depending on the preexisting behavioral state of the subject.
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.
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
Equivocal findings have been reported when opioid reward is assessed with the CPP
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,
and the potentiating effect of opioids on VTA intracranial self-stimulation is diminished
in animals with chronic pain.
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.
Strategies to restore dopamine signaling may represent a novel approach to manage
these affective sequelae of chronic pain.
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
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
(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.
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