Ноцицептин/Орфанин FQ: Ауырсынуды басу және мидың функцияларындағы ролі

Nociceptin/orphanin FQ (N/OFQ), a 17 amino acid neuropeptide, is the endogenous ligand for the nociceptin receptor (NOP, ORL 1). Nociceptin acts as a potent anti analgesic, effectively counteracting the effect of pain relievers; its activation is associated with brain functions such as pain sensation and fear learning. The gene coding for prepronociceptin is located on Ch8p21 in humans. Nociceptin is derived from the prepronociceptin protein, 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.

Since its discovery, nociceptin has been of great interest to researchers. Nociceptin is a peptide 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, brainstem, and forebrain, as well as in the ventral and dorsal horns of the spinal cord. The NOP receptor is also widely distributed throughout areas of the brain, including 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. This makes it unique from classic opioid peptides, which typically act as analgesics (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. When administered to the spinal cord, nociceptin produces similar analgesic effects to classical opioids.

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

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 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).

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 (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. A study at the University of Leicester 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.

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.