Nociceptin Anti-stress System Importance Confirmed

New findings from an international research collaboration confirms the importance of the brain system known as the nociceptin system, as a prospective target for therapies to treat stress-related conditions such as anxiety disorders.

“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 and principal investigator Marisa Roberto.

The substance nociceptin is produced in the brain, and is one of the opioid neurotransmitters. But there are many things that set it apart from the others.

Nociceptin binds to its own specific receptors called NOP receptors. It does not bind well to other opioid receptors. Scientists who discovered it in the mid-1990s also found the strange effect that when nociceptin is injected into the brains of mice, it doesn’t kill pain, it makes pain worse.

Antistress and other Properties

In due course, the molecule was named for this “nociceptive”, or pain-producing, effect. But later studies showed 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.

Possibly of foremost interest, several studies in rodents have found evidence that nociceptin can act in the amygdala, a part of the brain which 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 anti-stress feedback response.

Scientists have wanted to know more about the anti-stress activity of the nociceptin-NOP system, partially because it may provide 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.

Amygdala Studies

In this study, Roberto and her colleagues investigated in more detail at the nociceptin/NOP system in the central amygdala.

To begin with, Markus Heilig’s lab at the National Institute of Health measured the expression of NOP-coding genes in the central amygdala in rats.

Heilig’s team discovered good evidence that stress changes the activity of nociceptin/NOP in this region, showing that the system works as a feedback mechanism to damp the effects of stress. In animals subjected to standardized laboratory stress condition, NOP gene activity rose sharply, as if to compensate for the elevated stress.

Next, Roberto and her lab at The Scripps Research Institute used a different method to measure electrical activity of stress-sensitive neurons in the central amygdala.

As was the expectation, this neural activity rose when levels of the stress hormone Corticotrophin Releasing Factor (CRF) increased and even started out at higher levels in the stressed rats. This stress-sensitive neuronal activity, however, could be dialed down by adding nociceptin.

The stress-blocking effect was especially pronounced in the restraint-stressed rats, most likely because of their stress-induced increase in NOP receptors.

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

Over-activation Feedback Response

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.”

Roberto and her colleagues hope in future studies to find out 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.


R. Ciccocioppo, G. de Guglielmo, A. C. Hansson, M. Ubaldi, M. Kallupi, M. T. Cruz, C. S. Oleata, M. Heilig, M. Roberto.
Restraint Stress Alters Nociceptin/Orphanin FQ and CRF Systems in the Rat Central Amygdala: Significance for Anxiety-Like Behaviors.
Journal of Neuroscience, 2014; 34 (2): 363 DOI: 10.1523/JNEUROSCI.2400-13.2014