Monday, January 13, 2014

Nociceptin: Nature's Balm for the Stressed Brain

A new study was able to demonstrate the importance of the brain's stress-damping system, known as the nociceptin system. According to Wikipedia:
Nociceptin is an opioid-related peptide, but it does not act at the classic opioid receptors (namely, mu, kappa, and delta opioid receptors), and its actions are not antagonized by the opioid antagonist naloxone. Nociceptin is a potent anti-analgesic. Nociceptin is widely distributed in the CNS; it is found in many regions of the hypothalamus, brainstem, and forebrain, as well as in the ventral horn and dorsal horn of the spinal cord. Nociceptin acts at the Nociceptin receptor (NOP1), formerly known as ORL-1. The receptor is also widely distributed in the brain, including in the cortex, anterior olfactory nucleus, lateral septum, hypothalamus, hippocampus, amygdala, central gray, pontine nuclei, interpeduncular nucleus, substantia nigra, raphe complex, locus coeruleus, and spinal cord.
The new study shows that nociceptin anti-stress system to prevent and even reverse some of the cellular effects of acute stress in an animal model. The idea now is to know how to trigger this system so that we can use it therapeutically - it seems it would be really helpful in working with PTSD.

Full Citation: 
Ciccocioppo, R, de Guglielmo, G, Hansson, AC, Ubaldi, M, Kallupi, M, Cruz, MT, Oleata, CS, Heilig, M, and Roberto, M. (2014, Jan 8). 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

Nociceptin: Nature's Balm for the Stressed Brain

Jan. 8, 2014 — 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.

Here is the abstract from the original article, which is hidden from public view behind a paywall.

Restraint Stress Alters Nociceptin/Orphanin FQ and CRF Systems in the Rat Central Amygdala: Significance for Anxiety-Like Behaviors
Roberto Ciccocioppo1, Giordano de Guglielmo1, Anita C. Hansson2, Massimo Ubaldi1, Marsida Kallupi1,3, Maureen T. Cruz3, Christopher S. Oleata3, Markus Heilig4, and Marisa Roberto3

Author Affiliations
1. School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino 62032, Italy,
2. Institute of Psychopharmacology at the Central Institute of Mental Health, Medical Faculty Mannheim/University of Heidelberg, Heidelberg 68159, Germany,
3. Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, and
4. National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-1108
Author contributions: R.C., A.C.H., M.H., and M.R. designed research; R.C., G.d.G., A.C.H., M.K., M.T.C., C.S.O., and M.R. performed research; A.C.H. and M.U. analyzed data; R.C., M.H., and M.R. wrote the paper.


Corticotropin releasing factor (CRF) is the primary mediator of stress responses, and nociceptin/orphanin FQ (N/OFQ) plays an important role in the modulation of these stress responses. Thus, in this multidisciplinary study, we explored the relationship between the N/OFQ and the CRF systems in response to stress. Using in situ hybridization (ISH), we assessed the effect of body restraint stress on the gene expression of CRF and N/OFQ-related genes in various subdivisions of the amygdala, a critical brain structure involved in the modulation of stress response and anxiety-like behaviors. We found a selective upregulation of the NOP and downregulation of the CRF1 receptor transcripts in the CeA and in the BLA after body restraint. Thus, we performed intracellular electrophysiological recordings of GABAA-mediated IPSPs in the central nucleus of the amygdala (CeA) to explore functional interactions between CRF and N/OFQ systems in this brain region. Acute application of CRF significantly increased IPSPs in the CeA, and this enhancement was blocked by N/OFQ. Importantly, in stress-restraint rats, baseline CeA GABAergic responses were elevated and N/OFQ exerted a larger inhibition of IPSPs compared with unrestraint rats. The NOP antagonist [Nphe1]-nociceptin(1–13)NH2 increased the IPSP amplitudes in restraint rats but not in unrestraint rats, suggesting a functional recruitment of the N/OFQ system after acute stress. Finally, we evaluated the anxiety-like response in rats subjected to restraint stress and nonrestraint rats after N/OFQ microinjection into the CeA. Intra-CeA injections of N/OFQ significantly and selectively reduced anxiety-like behavior in restraint rats in the elevated plus maze. These combined results demonstrate that acute stress increases N/OFQ systems in the CeA and that N/OFQ has antistress properties.

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