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

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" 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 Gear.

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.

University of Southern California

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