Nociceptin: Nature’s Balm for the Stressed Brain

Collaborating scientists at The Scripps Research Institute (TSRI), the National Institutes of Health (NIH) and the University of Camerino in Italy have published new findings on a system in the brain that naturally moderates the effects of stress. The findings confirm the importance of this stress-damping system, known as the nociceptin system, as a potential target for therapies against anxiety disorders and other stress-related conditions.

“We were able to demonstrate the ability of this nociceptin anti-stress system to prevent and even reverse some of the cellular effects of acute stress in an animal model,” said biologist Marisa Roberto, associate professor in TSRI’s addiction research department, known as the Committee on the Neurobiology of Addictive Disorders.

Roberto was a principal investigator for the study, which appears in the January 8, 2014 issue of the Journal of Neuroscience.

A Variety of Effects

Nociceptin, which is produced in the brain, belongs to the family of opioid neurotransmitters. But the resemblance essentially ends there. Nociceptin binds to its own specific receptors called NOP receptors and doesn’t bind well to other opioid receptors. The scientists who discovered it in the mid-1990s also noted that when nociceptin is injected into the brains of mice, it doesn’t kill pain—it makes pain worse.

The molecule was eventually named for this “nociceptive” (pain-producing) effect. However, subsequent studies demonstrated that, by activating its corresponding receptor NOP, nociceptin acted as an antiopioid and not only affected pain perception, but also blocked the rewarding properties of opioids such as morphine and heroin.

Perhaps of greatest interest, several studies in rodents have found evidence that nociceptin can act in the amygdala, a part of the brain that controls basic emotional responses, to counter the usual anxiety-producing effects of acute stress. There have been hints, too, that this activity occurs automatically as part of a natural stress-damping feedback response.

Scientists have wanted to know more about the anti-stress activity of the nociceptin/NOP system, in part because it might offer a better way to treat stress-related conditions. The latter are common in modern societies, including post-traumatic stress disorder as well as the drug-withdrawal stress that often defeats addicts’ efforts to kick the habit.

Reducing the Stress Reaction

For the new study, Roberto and her collaborators looked in more detail at the nociceptin/NOP system in the central amygdala.

First, Markus Heilig’s laboratory at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the NIH, measured the expression of NOP-coding genes in the central amygdala in rats. Heilig’s team found strong evidence that stress changes the activity of nociceptin/NOP in this region, indicating that the system does indeed work as a feedback mechanism to damp the effects of stress. In animals subjected to a standard laboratory stress condition, NOP gene activity rose sharply, as if to compensate for the elevated stress.

Roberto and her laboratory at TSRI then used a separate technique to measure the electrical activity of stress-sensitive neurons in the central amygdala. As expected, this activity rose when levels of the stress hormone CRF rose and started out at even higher levels in the stressed rats. But this stress-sensitive neuronal activity could be dialed down by adding nociceptin. The stress-blocking effect was especially pronounced in the restraint-stressed rats—probably due to their stress-induced increase in NOP receptors.

Finally, biologist Roberto Ciccocioppo and his laboratory at the University of Camerino conducted a set of behavioral experiments showing that injections of nociceptin specifically into the rat central amygdala powerfully reduced anxiety-like behaviors in the stressed rats, but showed no behavioral effect in non-stressed rats.

The three sets of experiments together demonstrate, said Roberto, that “stress exposure leads to an over-activation of the nociceptin/NOP system in the central amygdala, which appears to be an adaptive feedback response designed to bring the brain back towards normalcy.”

In future studies, she and her colleagues hope to determine whether this nociceptin/NOP feedback system somehow becomes dysfunctional in chronic stress conditions. “I suspect that chronic stress induces changes in amygdala neurons that can contribute to the development of some anxiety disorders,” said Roberto.

Compounds that mimic nociceptin by activating NOP receptors—but, unlike nociceptin, could be taken in pill form—are under development by pharmaceutical companies. Some of these appear to be safe and well tolerated in lab animals and may soon be ready for initial tests in human patients, Ciccocioppo said.

Researchers find out why some stress is good for you

Overworked and stressed out? Look on the bright side. Some stress is good for you.

“You always think about stress as a really bad thing, but it’s not,” said Daniela Kaufer, associate professor of integrative biology at the University of California, Berkeley. “Some amounts of stress are good to push you just to the level of optimal alertness, behavioral and cognitive performance.”

New research by Kaufer and UC Berkeley post-doctoral fellow Elizabeth Kirby has uncovered exactly how acute stress – short-lived, not chronic – primes the brain for improved performance.

In studies on rats, they found that significant, but brief stressful events caused stem cells in their brains to proliferate into new nerve cells that, when mature two weeks later, improved the rats’ mental performance.

“I think intermittent stressful events are probably what keeps the brain more alert, and you perform better when you are alert,” she said.

Kaufer, Kirby and their colleagues in UC Berkeley’s Helen Wills Neuroscience Institute describe their results in a paper published April 16 in the new open access online journal eLife.

The UC Berkeley researchers’ findings, “in general, reinforce the notion that stress hormones help an animal adapt – after all, remembering the place where something stressful happened is beneficial to deal with future situations in the same place,” said Bruce McEwen, head of the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at The Rockefeller University, who was not involved in the study.

Kaufer is especially interested in how both acute and chronic stress affect memory, and since the brain’s hippocampus is critical to memory, she and her colleagues focused on the effects of stress on neural stem cells in the hippocampus of the adult rat brain. Neural stem cells are a sort of generic or progenitor brain cell that, depending on chemical triggers, can mature into neurons, astrocytes or other cells in the brain. The dentate gyrus of the hippocampus is one of only two areas in the brain that generate new brain cells in adults, and is highly sensitive to glucocorticoid stress hormones, Kaufer said.

Much research has demonstrated that chronic stress elevates levels of glucocorticoid stress hormones, which suppresses the production of new neurons in the hippocampus, impairing memory. This is in addition to the effect that chronically elevated levels of stress hormones have on the entire body, such as increasing the risk of chronic obesity, heart disease and depression.

Less is known about the effects of acute stress, Kaufer said, and studies have been conflicting.

To clear up the confusion, Kirby subjected rats to what, to them, is acute but short-lived stress – immobilization in their cages for a few hours. This led to stress hormone (corticosterone) levels as high as those from chronic stress, though for only a few hours. The stress doubled the proliferation of new brain cells in the hippocampus, specifically in the dorsal dentate gyrus.

Kirby discovered that the stressed rats performed better on a memory test two weeks after the stressful event, but not two days after the event. Using special cell labeling techniques, the researchers established that the new nerve cells triggered by the acute stress were the same ones involved in learning new tasks two weeks later.

“In terms of survival, the nerve cell proliferation doesn’t help you immediately after the stress, because it takes time for the cells to become mature, functioning neurons,” Kaufer said. “But in the natural environment, where acute stress happens on a regular basis, it will keep the animal more alert, more attuned to the environment and to what actually is a threat or not a threat.”

They also found that nerve cell proliferation after acute stress was triggered by the release of a protein, fibroblast growth factor 2 (FGF2), by astrocytes — brain cells formerly thought of as support cells, but that now appear to play a more critical role in regulating neurons.

“The FGF2 involvement is interesting, because FGF2 deficiency is associated with depressive-like behaviors in animals and is linked to depression in humans,” McEwen said.

Kaufer noted that exposure to acute, intense stress can sometimes be harmful, leading, for example, to post-traumatic stress disorder. Further research could help to identify the factors that determine whether a response to stress is good or bad.

“I think the ultimate message is an optimistic one,” she concluded. “Stress can be something that makes you better, but it is a question of how much, how long and how you interpret or perceive it.”