The Yin and Yang of Pain and Pleasure

by Jim Schnabel

August 21, 2008

Pain and pleasure are our primary motivators, and neuroscience has only begun to untangle the intricacies of how they act upon us. It has long been assumed, for example, that these opposing sensations are delivered by distinct networks in the nervous system. However, researchers in the emerging scientific field of hedonics are finding that pain and pleasure pathways have much in common.

“Sometimes you have a competition in which, for instance, you want to seek some reward but you can only do that at the price of pain,” says Siri Leknes, a neuroscientist at the University of Oslo who co-authored a review paper on pain-pleasure interactions in the April issue of Nature Reviews Neuroscience. “You have to be able to compare those two competing motivations, so there has to be some sort of interaction in the brain where such a comparison is made. And it is beginning to seem that pain and pleasure are being compared not just in one central region but virtually throughout their respective networks, which biologically share several key features.”

The hedonic spectrum

“The question is whether pain and pleasure are two different things, or are part of the same spectrum,” says University of Michigan neuroscientist Jon-Kar Zubieta. “For example, if somebody is in pain for a long period of time or under high levels of stress, they release endogenous opioids. They will feel less pain; they control the pain better. But this system also becomes activated when you receive drugs of abuse, for example, and you feel pleasure.”

Studies in animals and humans over the past two decades have shown that even ordinary stimuli such as food and sex simultaneously bring pleasure and reduce ambient pain, apparently by triggering the release, into key brain areas, of these natural morphine-like neurotransmitters.

The human brain has evolved such a capacity for anticipating events that the mere expectation of a pleasurable reward can trigger endogenous-opioid analgesia. This is the basis of the placebo effect, which in the past few years has been traced, using PET and fMRI imaging techniques, to the release of opioids known as μ-opioids in the limbic system and frontal cortex.

Initiating this opioid release are spurts of dopamine in the same areas, which form part of a loop of nerves from the cortex through the midbrain and limbic regions and back to the cortex again. This February the Archives of General Psychiatry published the results of a PET-based study, led by David Scott from Zubieta’s laboratory, in which the ability of a placebo to reduce pain in volunteer subjects was stronger when dopamine and μ-opioids were more active in these key brain areas—and was weaker when these neurotransmitters were less active.

Some subjects paradoxically reported greater pain after receiving the placebo (an outcome researchers call the “nocebo” effect) and in these cases the usual analgesia-related dopamine and opioid responses appeared to have ceased altogether.

There is evidence that the pain-pleasure interaction works the other way too, so that pain reduces the ability to experience pleasure.

“This area hasn’t been as well studied,” says Leknes, “but chronic pain typically causes reduced feeding in animals, and the effect is reversible with morphine. Also, people who experience chronic pain often suffer from depression and lose the ability to experience everyday pleasures.”

Untangling the relationship between dopamine and the endogenous opioids remains a major target of research focus. In animal studies, for example, dopamine appears to be involved in the brain’s “wanting” a reward, while opioids are associated with the actual enjoyment. Scott sees dopamine surges in the ventral striatum as indications of the raw importance or “salience” of a stimulus, whether good or bad. At the same time, it appears almost always to trigger endogenous opioids—but the strength of that response seems to depend on whether a reward is perceived in the situation.

Precisely how endogenous opioids go about modulating pleasure and pain at the same time is another unresolved question. But brain imaging studies indicate that in the orbitofrontal cortex, the amygdala and the ventral striatum, neurons whose activity correlates with feelings of pain and pleasure exist in close proximity—so that endogenous opioids, for example, may affect both populations simultaneously.

“It’s not yet known whether they do, but it’s certainly compelling that separate neuronal populations do seem to exist within these regions,” says Leknes.


Pleasure as a direction, not a destination

If the powers of endogenous opioids, or their apparent dopamine triggers, could be harnessed effectively, could life be a blissful, pain-free mental paradise? Various intensely pleasurable behaviors have offered humans a seductive glimpse of such a realm. But hedonics research suggests that this goal is more in the nature of a mirage—disallowed by evolution because the brains that achieved it would be deeply maladaptive.

Pain and pleasure, in other words, are meant to be steering signals rather than destinations in themselves. Thus, attempts to reach the Nirvana of chronic pleasure seem only to end up producing a blunting of feeling—much like that associated with chronic pain.

A hit of a recreational drug, for example, typically causes a tremendous spike in dopamine levels in the motivational hotspots of the brain, with a corresponding rush of endogenous opioids. But the brain is meant to maintain a more-or-less constant dynamic range for the activity of these hugely important systems: Its relevant neurons respond to a chronic overabundance of neurotransmitter molecules in effect by becoming less sensitive to them. More and more of the drug is needed to produce the same euphoric effect, and eventually it is needed just to feel normal.

“The dopamine system is not meant to be cranked up to full and left on for a period,” says David Scott. “You crank it up to such an extent [with drug abuse] that you change it in a fundamental way, and now merely natural things are unable to take it to that level.”

In principle this diminishing-returns problem applies to any deeply pleasurable stimulus. “Even people who engage in extreme sports may have a reduced ability to enjoy ordinary pleasures,” says Leknes, citing a study in 2006 by Ingmar Franken and colleagues at the University of Erasmus in Rotterdam, who found that a group of skydivers reported more anhedonia symptoms than a group of rowers.

The hedonic personality

Just as extreme behaviors might in principle be able to derange the brain’s responsiveness to the stimuli of ordinary life, innate individual differences in that responsiveness appear to underlie a range of behaviors and behavior-related disorders.

For example, David Scott and his colleagues, in their placebo/nocebo study, found considerable variation among their subjects in the way that they responded to the placebo stimuli. Some reported that they felt significant analgesia; others felt worsening pain. A significant part of that variation appeared to be accounted for by differences in short-term dopamine surges in an area of the ventral striatum known as the nucleus accumbens, long known as a reward- and pleasure-sensitive zone.

Such short-term, “phasic” responsivity to stimuli is now known to be partly controlled by the background, or “tonic” level of dopamine in these areas. When the relevant neurons detect a high level of tonic dopamine, they tend to reduce their short-term, phasic responsivity to stimuli, thus effectively dulling sensation and motivation. Low tonic dopamine, on the other hand, tends to lead to enhanced, even “hyper” responsivity, so that even relatively humdrum stimuli are apt to hit the brain hard.

“Whenever you have low tonic dopamine, one thing you’re going to get is perseverative behavior, where people tend to have problems breaking out of a routine,” says Anthony Grace, a neuroscientist at the University of Pittsburgh.

Such hyper-responsivity to stimuli also has been associated with psychosis, and Grace and his colleagues have been studying the possibility that schizophrenia is at least partly caused by an abnormal dopamine-responsivity that also affects the hedonic and motivational systems.

Zubieta’s laboratory, meanwhile, has reported finding associations between dysfunctions in these systems and conditions including depression, fibromyalgia and psychological trauma.

Leknes for her part plans to study individual variations in reward and punishment sensitivity in the ordinary population, and how these differences develop in childhood. “Different people are differently sensitive to cues of reward and punishment in their environment, and I want to find out why,” she says.