NociceptinOrphaninFQ

Discovery

Nociceptin/orphanin FQ was first identified as an endogenous ligand for a GPCR that is homologous to opioid receptors. A 17-aa peptide that decreased forskolinstimulated cAMP production in vitro was isolated from the rat brain in 1995 and named N, based on its ability to increase reactivity to pain. The isolation of a peptide with an identical sequence from the porcine brain was simultaneously reported, and this peptide was named OFQ. The term orphanin refers to the affinity of the peptide for an orphan opioid receptor, and F and Q reflect the N- and C-terminal amino acid residues, respectively.

Structure

N/OFQ is generated from the precursor pronociceptin by proteolytic cleavage. The amino acid sequence of N/OFQ is common among the human, rat, and mouse. The N-terminal pentapeptide sequence of N/OFQ, Phe-Gly-Gly-Phe-Thr, is related to those of Met-enkephalin (Tyr-Gly-Gly-Phe-Met) and Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu)

Gene, mRNA, and precursor

The human prepronociceptin gene, PNOC, location 8q21, consists of four exons, and two cAMP responsive elements are involved in the regulation of gene expression. Human preproN/OFQ (ppN/PFQ) is composed of 167 aa residues, with a signal peptide consisting of 19 aa residues followed by a cysteine-containing the N-terminal sequence and the region containing N/OFQ.

Synthesis and release

A TATA-box motif upstream of the human PNOC gene displays weak promoter activity. An increase of cellular cAMP levels by forskolin treatment upregulates PNOC transcription. Estrogen also upregulates PNOC transcription, whereas glucocorticoid downregulates transcription.

Receptors

N/OFQ is an agonist for N/OFQ receptors (NOP, also known as nociceptin receptor, opiate receptor-like 1 [OPRL1], ORL receptor, ORL-1, N/OFQ receptor, etc.), which are a subtype of opioid receptors belonging to the GPCR family. Human OPRL1 is located on chromosome 20 (20q13.33).

Agonists and Antagonists

UFP-102, Ro64-6198, and Ac-RYYRIK-NH2 are agonists. UFP-101, SB 612111, J-113397, and JTC-801 are antagonists.

Biological functions

The first behavioral effect of N/OFQ to be described was a hyperalgesic response (lowering of nociceptive thresholds). However, the effect of N/OFQ on nociceptive responses is complicated, as various studies report hyperalgesia, blockade of hyperalgesia, analgesia, blockade of analgesia, no effect, or blockade of allodynia in response to N/OFQ. N/OFQ is also associated with locomotion, feeding, anxiety, spatial attention/learning, endocrine effects in the hypothalamus, reward, and opiate tolerance and dependence. N/OFQ reduces dopamine levels in the nucleus accumbens in rats, whereas it increases dopamine release in the striatum. N/OFQ also inhibits the release of acetylcholine from the guinea pig trachea, substance P and the calcitonin gene-related peptide from sensory nerve endings, and glutamate from cerebrocortical slices in rats. N/OFQ stimulates prolactin release in both sexes, but the effect is much greater in females. Conversely, growth hormone release is stimulated only in male rats. The peptide inhibits electrically induced contractions of both the guinea pig ileum and the mouse vas deferens. N/OFQ causes hypotension and bradycardia in anesthetized rats, whereas it increases the blood pressure and heart rate in unanesthetized ewes.

Clinical implications

The endogenous N/OFQ system has a physiological role in mediating or regulating behavioral responses to alcohol, and the activation of NOP suppresses ongoing alcohol consumption or the reinstatement of responding to alcohol. These findings encourage the development of therapies targeted at the N/OFQ system for the treatment of alcoholism in humans.

Description

Nociceptin/orphanin FQ,, An opioid peptide that is evolutionarily related to dynorphin and enkephalin, N/OFQ is a heptadecapeptide exhibiting hyperalgesic action—i.e., a decrease in the nociceptive threshold.