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Definition
Nociceptin is a 17 amino acid opioid-like peptide that was identified as a natural ligand of the orphan opioid receptor ORL1 (also referred to as OP4). Reinscheid et al., called the same peptide orphanin FQ to signify that it is a ligand for ORL1 with an N-terminal phenylalanine and a C-terminal glutamine 1.


Related peptides
The prepronociceptin gene also encodes another peptide, termed nocistatin. Nocistatin blocks allodynia and hyperalgesia induced by Nociceptin and attenuates pain evoked by prostaglandin E2. Nocistatin does not bind to the Nociceptin receptor. Nociceptin and nocistatin may play opposite roles in pain transmission 2. Nociceptin is related to dynorphin A, a peptide 17-mer ligand of the -opioid receptor. Dynorphin A also binds ORL1 but with 100-fold lower affinity than nociceptin . Orphanin FQ2 is another biologically active peptide 17-mer processed from the same nociceptin precursor, prenociceptin 1.


Discovery
Civelli et al., in 1998, reported the discovery of a peptide ligand that shares some striking sequence similarity to the opioid peptides and named it Orphanin FQ or Nociceptin (OFQ/NOC) 3.


Structural Characteristics
Nociceptin is a 17 amino acid neuropeptide. The full pharmacophore site for nociceptin has the phenyl ring of Phe1 on top of that for Phe4. The first turn of the helix places Phe4 over Ala7 and Arg8 followed by the second turn of the helix with another Ala-Arg pair, Ala11 and Arg12. This fold causes the two pairs of alanine-arginine residues, both of which appear to be crucial to activity, to lie on top of one another. This finding suggests that nociceptin when folded in this fashion interacts with ORL1 via both hydrophobic residues and positively charged residues. As mentioned above, it also appears that the hydrogen bonding potential of the arginine guanidinium group and not only its positive charge plays a role in the activity of nociceptin 1.


Nociceptin Fragments
The nociceptin N-terminal fragments, (1–11) and (1–13), are active with a potency higher than nociceptin and comparable to nociceptin, respectively. The nociceptin (1–7) fragment had no effect on capsaicin-induced nociception. Nociceptin (1–11) is approximately 2.0-fold more potent than naturally occurring peptide nociceptin, and 10-fold more active than intraplantar morphine. Nociceptin and the N-terminal fragment (1–13) possess a local peripheral antinociceptive action, which may be mediated by peripheral ORL1 receptors. In addition, the antinociceptive action and inhibition of capsaicin-induced desensitization by nociceptin, nociceptin (1–11) and (1–13), may involve distinct mechanisms at the level of the peripheral nerve  terminal 4.


The minimal fragment sequence required to fully activate the nociceptin (NC) receptor, namely NC(1-13)-NH2, was used as template for the design of a series of new compounds. Changes were made in the N-terminal tetrapeptide Phe-Gly-Gly-Phe, which has been shown to be essential for receptor occupation and activation. The new compounds were tested for their ability to inhibit the electrically evoked contraction of the mouse vas deferens, a pharmacological preparation sensitive to NC. Results obtained indicate that (a) the replacement of Gly2 or Gly3 with an aromatic residue (Phe) of L or D chirality eliminates the ability of the peptide to occupy the NC receptor; (b) the distance between Phe1 and Phe4 of NC appears to be critical, since any alteration of it leads to a marked decrease or a total elimination of biological activity; and (c) the insertion of a pseudopeptide bond between Phe1 and Gly2 maintains affinity but eliminates the ability of the peptide to activate the NC receptor and leads to antagonism. The peptide [Phe1?(CH2-NH)Gly2]-NC(1-13)-NH2 acts as a selective NC receptor antagonist and is inactive on opioid receptors 5.


Mechanism of action
Meunier et al., (1995) and Reinscheid et al., (1995) have shown that nociceptin is a physiological ligand for an orphan heterotrimeric GTP-binding protein6,7. This protein was identified originally as the G-protein-coupled receptor LC1328. Mollereau et al., (1994) have cloned the human nociceptin receptor, a G-protein-coupled receptor of 370 amino acids most closely related to opioid receptors. The receptor is known also as NOCIR [nociceptin receptor] OPRL1 or ORL1 [opioid receptor-like-1], OP4, or NOP [non-classical opioid receptor] 9.


Functions
Nociceptin signaling through ORL1 elicits many of the same responses induced by opioid signaling through the opioid receptors. Nociceptin causes inhibition of adenylyl cyclase, activation of potassium channels, inhibition of calcium channels, mobilization of intracellular calcium, and activation of mitogen-activated protein kinase. These effects indicate that, similar to opioids, nociceptin has an inhibitory effect on synaptic transmission in the nervous system, acting to reduce the secretion of neurotransmitters. Consistent with its cellular effects, nociceptin inhibits the release of glutamate, -Aminobutyric acid, acetylcholine, tachykinin, and noradrenaline neurotransmitters. Based on their distribution in the brain and spinal cord, nociception and its receptor may be involved in a wide range of functions, including learning, memory, attention, and emotion. Nociceptin is also implicated in various sensory processes such as perception of pain, visual, auditory, and olfactory functions1.


References

1.     Orsini MJ, Nesmelova I, Young HC, Hargittai B, Beavers MP, Liu J, Connolly PJ, Middleton SA, Mayo KH (2005). The Nociceptin Pharmacophore Site for Opioid Receptor Binding Derived from the NMR Structure and Bioactivity Relationships. J. Biol. Chem., 280(9):8134-8142.

2.      Okuda-Ashitaka E, Minami T, Tachibana S, Yoshihara Y, Nishiuchi Y, Kimura T, Ito S (1998). Nocistatin, a peptide that blocks Nociceptin action in pain transmission. Nature, 392(6673):286-289.

3.     Civelli O, Nothacker HP, Reinscheid R (1998). Reverse physiology: discovery of the novel neuropeptide, orphanin FQ/nociceptin. Crit Rev Neurobiol., 12(3):163-176.

4.     Sakurada T, Komatsu T, Moriyama T, Sasaki M, Sanai K, Orito T, Sakurada C, Sakurada S (2005). Effects of intraplantar injections of nociceptin and its N-terminal fragments on nociceptive and desensitized responses induced by capsaicin in mice. Peptides, 26(12):2505-2512.

5.     Calo G, Guerrini R, Bigoni R, Rizzi A, Bianchi C, Regoli D, Salvadori S (1998). Structure-activity study of the Nociceptin(1-13)-NH2 n-terminal tetrapeptide and discovery of a nociceptin receptor antagonist. J medi chem., 41(18):3360-3366.

6.     Meunier JC, Mollereau C, Toll L, Suaudeau C, Moisand C, Alvinerie P, Butour JL, Guillemot JC, Ferrara P, Monsarrat B (1995). Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature, 377(6549):532-535.

7.     Reinscheid RK, Nothacker HP, Bourson A, Ardati A, Henningsen RA, Bunzow JR, Grandy DK, Langen H, Monsma FJ Jr, Civelli O (1995). Orphanin FQ: a neuropeptide that activates an opioid-like G protein-coupled receptor. Science,  270(5237):792-794.

8.     Bunzow JR, Saez C, Mortrud M, Bouvier C, Williams JT, Low M, Grandy DK (1994). Molecular cloning and tissue distribution of a putative member of the rat opioid receptor gene family that is not a mu, delta or kappa opioid receptor type. FEBS Letters., 347(2-3): 284-288.

9.     Mollereau C, Parmentier M, Mailleux P, Butour JL, Moisand C, Chalon P, Caput D, Vassart G, Meunier JC (1994). ORL1, a novel member of the opioid receptor family: cloning, functional expression and localization. FEBS Letters., 341:33-38.

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