Nociceptin/orphanin FQ (N/OFQ), a 17-

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

neuropeptide Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...

, is the endogenous

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

for the nociceptin receptor (NOP, ORL-1). Nociceptin acts as a potent anti-

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

, effectively counteracting the effect of pain-relievers; its activation is associated with brain functions such as pain sensation and fear learning. The

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

coding for prepronociceptin is located on Ch8p21 in humans. Nociceptin is derived from the prepronociceptin

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

, as are a further two peptides, nocistatin and NocII, both of which inhibit N/OFQ receptor function. Nociceptin is the first example of reverse pharmacology; the NOP receptor was discovered before the endogenous ligand which was discovered by two separate groups in 1995.

Roles of nociceptin

Since its discovery, nociceptin has been of great interest to researchers. Nociceptin is a

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

related to the kappa opioid receptor ligand dynorphin A, but it does not act at the classic opioid receptors (namely, mu, kappa, and delta opioid receptors) which typically act as pain relievers. Nociceptin is widely distributed in the CNS; it is found in the

hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...

brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is conti ...

, and

forebrain In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the rostral (forward-most) portion of the brain. The forebrain controls body temperature, reproductive functions, eating, sleeping, and the display of emotions. Ve ...

, as well as in the ventral and dorsal horns of the

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...

. The NOP receptor is also widely distributed throughout areas of the brain, including the

cortex Cortex or cortical may refer to: Biology * Cortex (anatomy), the outermost layer of an organ ** Cerebral cortex, the outer layer of the vertebrate cerebrum, part of which is the ''forebrain'' *** Motor cortex, the regions of the cerebral cortex i ...

, anterior olfactory nucleus, lateral

septum In biology, a septum (Latin language, Latin for ''something that encloses''; septa) is a wall, dividing a Body cavity, cavity or structure into smaller ones. A cavity or structure divided in this way may be referred to as septate. Examples Hum ...

hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...

amygdala The amygdala (; : amygdalae or amygdalas; also '; Latin from Greek language, Greek, , ', 'almond', 'tonsil') is a paired nucleus (neuroanatomy), nuclear complex present in the Cerebral hemisphere, cerebral hemispheres of vertebrates. It is c ...

, central gray, pontine nuclei, interpeduncular nucleus,

substantia nigra The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts of the substantia nigra a ...

, raphe complex, locus coeruleus, and

Pain

The N/OFQ-NOP system is found in central and peripheral nervous tissue, where it is well placed to modulate

nociception In physiology, nociception , also nocioception; ) is the Somatosensory system, sensory nervous system's process of encoding Noxious stimulus, noxious stimuli. It deals with a series of events and processes required for an organism to receive a pai ...

, or the body's sensation of pain. Unlike morphine and other opioids that are used to alleviate pain, nociceptin's role in nociception is not straightforward. Administration of N/OFQ in the brain causes increased sensations of pain (

hyperalgesia Hyperalgesia ( or ; ''hyper'' from Greek ὑπέρ (''huper'') 'over' + ''-algesia'' from Greek ἄλγος (algos) 'pain') is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and ...

). This makes it unique from classic opioid peptides, which typically act as

s (pain relievers), as it means that nociceptin can even counteract analgesia, thus acting as an antiopioid. Additionally, blocking the nociceptin receptor can lead to an increased pain threshold and a decreased tolerance development to analgesic opioids. As such, nociceptin has a lower risk of addiction than many pain relievers that are currently used. Recent studies have proposed that this anti-analgesic function of nociceptin stems from the inhibition of the periaqueductal grey, which controls pain modulation from the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

. This effect of nociceptin may lead to its future use as a method to reduce morphine dosage and decrease the development of tolerance and dependence. When administered to the spinal cord, nociceptin produces similar analgesic effects to classical opioids.

Mood disorders

There are various studies on animals that suggest that the N/OFQ-NOP system has a part to play in both anxiety and depression. It appears that nociceptin is an

anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...

(anxiety inhibitor) but also seems to perpetuate depression, since preventing N/OFQ from binding to NOP seems to improve depression.

Drug abuse medications

The NOP receptor has shown potential as a target for medications designed to alleviate the effects of substance abuse disorders. Areas in the hypothalamus and amygdala that correlate to the reward process of drug abuse have been found to contain NOP receptors. Nociceptin has also been found to inhibit dopamine production related to the reward process. Specifically, nociceptin acts to inhibit neural rewards induced by drugs such as amphetamines, morphine, cocaine, and especially

alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

in animal models, though the exact mechanism of this has not yet been proven. Additionally, nociceptin may have lower tolerance development than drugs such as morphine. This was shown when nociceptin compounds were used as a pain medication substitution for morphine. Nociceptin also has therapeutic capabilities for addictions to multiple drugs, potentially playing a role in compounds that have decreased withdrawal tendencies (such as muscle aches, anxiety, and restlessness).

Learning and memory

In animal studies, the N/OFQ-NOP receptor pathway has also been found to play both positive and negative roles in both learning and memory. For example, malfunctions in this pathway are linked to altered fear learning in brain disorders such as

post-traumatic stress disorder Post-traumatic stress disorder (PTSD) is a mental disorder that develops from experiencing a Psychological trauma, traumatic event, such as sexual assault, domestic violence, child abuse, warfare and its associated traumas, natural disaster ...

(PTSD). As such, the receptor pathway maintains homeostatic responses to fear and stressful situations. Nociceptin could also play an inhibitory role in memory function, as some studies show that it impairs spatial learning ''in vivo'', while inhibiting long term potentiation and synaptic transmission ''in vitro''.

Cardiovascular system

The N/OFQ-NOP system has also been implicated in control of the cardiovascular system, as nociceptin administration has led to high blood pressure and

bradycardia Bradycardia, also called bradyarrhythmia, is a resting heart rate under 60 beats per minute (BPM). While bradycardia can result from various pathological processes, it is commonly a physiological response to cardiovascular conditioning or due ...

. Nociceptin has significant effects on cardiovascular parameters such as blood pressure and heart rate that vary by species, as it is excitatory for rodents yet inhibitory for sheep.

Renal system

In the renal system, nociceptin plays a role in water balance, electrolyte balance, and arterial blood pressure regulation. It has also shown potential as a diuretic treatment for alleviating water-retaining diseases.

Immune system

Additional research suggests that nociceptin may be involved in the immune system and

sepsis Sepsis is a potentially life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage of sepsis is followed by suppression of the immune system. Common signs and s ...

. A study at the

University of Leicester The University of Leicester ( ) is a public university, public research university based in Leicester, England. The main campus is south of the city centre, adjacent to Victoria Park, Leicester, Victoria Park. The university's predecessor, Univ ...

looked at patients who were critically ill with sepsis and found that blood N/OFQ levels were significantly higher in patients who died within thirty days in comparison to survivors.

Digestive system

In the gut, nociceptin has been found to have varying effects on stomach and intestinal contractility while also stimulating the increased consumption of food. Additional studies have shown that nociceptin may have an effect as an anti-epileptic drug component.

References

External links

* * {{Opioidergics Neuropeptides Opioid peptides Nociceptin receptor agonists Opioids