Mesolimbic dopamine signaling in acute and chronic pain: implications for motivation, analgesia, and addiction – Pain. 2016 Jun – free full-text PMC article
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.
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.
- 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, or for both aversive and rewarding stimuli.
These neurons are probably responsible for the dopamine release after aversive stimuli, such as psychosocial stress or pain
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 processing
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
- 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.
However, more often, no effects of dopaminergic manipulations on a variety of pain tests have been reported
Examining under which conditions antinociception is mostly observed suggests that the common feature is a motivational–emotional component of the pain tests
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.
This framework means that dopamine would play a crucial role in
- pain avoidance and
- coping responses,
processes that are of high clinical importance.
- 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
In animal studies, chronic pain results in decreased c-Fos activation in the VTA42 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
…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 levels.
Taken together, these results indicate that chronic pain leads to a significant impairment of mesolimbic dopamine activity that interferes with motivated behavior.
- 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.
On a mechanistic level, opioids are less effective at stimulating mesolimbic dopamine neurons in 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
Taken together, we conclude that although the mesolimbic dopamine system is less responsive in chronic pain, systemic opioids remain reinforcing through their analgesic effects.
This means we are motivated to take opioids by the need for pain relief, not the desire for euphoria.
Importantly, analgesia seems to be required for systemic opioids to be reinforcing in chronic pain.
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.
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 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.
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