By Jennifer O'Brien

Researchers have long known that the body can activate its own form of pain
relief in response to painful stimuli. Now, UC San Francisco investigators have
determined that, in rats, this long-lasting relief is produced by the brain’s
“reward” pathway—the neural circuitry activated by drugs of abuse.

In their study, published in the August 15 issue of Journal of Neuroscience,
the investigators determined that, at its maximum, the pain relief was as
potent as a high dose of morphine.

While various individual structures in the brain have been known to produce
analgesia, or pain relief, when electrically stimulated or exposed to narcotic
painkillers, the finding provides the first physiological evidence that pain
itself elicits analgesia. 

It also provides a surprising twist on the perceived workings of the neural
circuitry associated with gratification, said the lead author of the study,
Robert W. Gear, PhD, assistant clinical professor of Oral and Maxillofacial
Surgery in the NIH Pain Center at UCSF. 

“We’re showing that something aversive—exposure to a painful stimulus—as
well as exposure to drugs of abuse, stimulate the same reward circuit,” said
Gear, whose lab is directed by senior author Jon D. Levine, MD, PhD, a
professor of Oral and Maxillofacial Surgery and Medicine and director of the
NIH Pain Center.

“Our result casts new light on how to look at the key structure in the reward
pathway, the nucleus accumbens, and the role it plays in affirming certain
behaviors and thus motivating individuals to act in particular ways,” said

The reward pathway is a neural network in the middle of the brain that prompts
good feelings in response to certain behaviors, such as relieving hunger,
quenching thirst or having sex, and it thereby reinforces these evolutionarily
important drives. However, the circuit also responds to drugs of abuse, such as
heroin, cocaine, amphetamine and nicotine, which seem to hijack the circuitry,
altering the behavior of its neurons.

The nucleus accumbens is the engine of the reward response. And, in their
study, the UCSF researchers determined that the reward pathway activates pain
relief through the release of both opioids, a morphine-like drug produced by
the body, and dopamine, a chemical messenger whose effects can be mimicked by
amphetamine and cocaine, in this structure.  The finding overturns the
long-held assumption that the release of dopamine in the nucleus accumbens is
associated only with positive experiences.

The evolutionary value of a rush of analgesia is clear, as it could allow, for
example, a badly injured individual to escape an attacker.  It probably could
also explain why some individuals can be injured without persistent pain.

But the phenomenon may also explain why heroin addicts, in withdrawal, can
experience pain or increased sensitivity to painful stimuli. “It may be that
one of the reasons people stay addicted is to avoid going through this
unpleasant state of withdrawal,” said Gear.

Under other conditions, it’s possible that a painful stimulus, by activating
the nucleus accumbens, might itself be experienced as rewarding, as appears to
occur in self-injurious behaviors. Interestingly, treatment for this class of
disorders, characterized by pursuit of painful experiences often for apparent
thrill-seeking value, includes administration of naloxone, a drug that blocks
the effects of opioids in this reward circuit.

The researchers conducted the bulk of their study in anesthetized rats,
measuring the animals’ response to pain signals in the paws.  Because these
animals were anesthetized, the measurements were taken using a technique known
as the jaw-opening reflex, in which the degree to which the jaw opens
reflexively in response to painful stimuli to the tooth indicates the level of
pain experienced.  The jaw-opening reflex decreased, a sign of analgesia, as
the painful stimulus increased.

The fact that the analgesic effect was demonstrated in the teeth, far from the
hindpaw, indicated its general effect in the whole body.  The analgesic effects
did not require repeated application of the stimuli, and were shown to last at
least an hour.

“Our results were quite dramatic,” said senior author Levine. “They’ve spawned
several new studies in our lab aimed at revealing more about the role of the
reward pathway, and the nucleus accumbens specifically, in human behaviors.”

The other co-author of the study was K.O. Aley, PhD, of the UCSF Department of
Oral and Maxillofacial Surgery. 

The UCSF study was funded by the State of California Tobacco-Related Diseases
Research program.