Pain, Itself, Elicits Pain Relief, And Does So Through "Reward" Pathway

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

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

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

"We're showing that something aversive -- exposure to a painful stimulus -- aswell as exposure to drugs of abuse, stimulate the same reward circuit," saidGear, whose lab is directed by senior author Jon D. Levine, MD, PhD, aprofessor of Oral and Maxillofacial Surgery and Medicine and director of theNIH Pain Center.

"Our result casts new light on how to look at the key structure in the rewardpathway, the nucleus accumbens, and the role it plays in affirming certainbehaviors and thus motivating individuals to act in particular ways," saidGear.

The reward pathway is a neural network in the middle of the brain that promptsgood feelings in response to certain behaviors, such as relieving hunger,quenching thirst or having sex, and it thereby reinforces these evolutionarilyimportant drives. However, the circuit also responds to drugs of abuse, such asheroin, 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 theirstudy, the UCSF researchers determined that the reward pathway activates painrelief through the release of both opioids, a morphine-like drug produced bythe body, and dopamine, a chemical messenger whose effects can be mimicked byamphetamine and cocaine, in this structure. The finding overturns thelong-held assumption that the release of dopamine in the nucleus accumbens isassociated only with positive experiences.

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

But the phenomenon may also explain why heroin addicts, in withdrawal, canexperience pain or increased sensitivity to painful stimuli. "It may be thatone of the reasons people stay addicted is to avoid going through thisunpleasant state of withdrawal," said Gear.

Under other conditions, it's possible that a painful stimulus, by activatingthe nucleus accumbens, might itself be experienced as rewarding, as appears tooccur in self-injurious behaviors. Interestingly, treatment for this class ofdisorders, characterized by pursuit of painful experiences often for apparentthrill-seeking value, includes administration of naloxone, a drug that blocksthe 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 theseanimals were anesthetized, the measurements were taken using a technique knownas the jaw-opening reflex, in which the degree to which the jaw opensreflexively in response to painful stimuli to the tooth indicates the level ofpain experienced. The jaw-opening reflex decreased, a sign of analgesia, asthe painful stimulus increased.

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

"Our results were quite dramatic," said senior author Levine. "They've spawnedseveral new studies in our lab aimed at revealing more about the role of thereward 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 ofOral and Maxillofacial Surgery.

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