Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor

Abstract

The ORL1 receptor, an orphan receptor whose human and murine complementary DNAs have recently been characterized, structurally resembles opioid receptors and is negatively coupled with adenylate cyclase. ORL1 transcripts are particularly abundant in the central nervous system. Here we report the isolation, on the basis of its ability to inhibit the cyclase in a stable recombinant CHO(ORL1+) cell line, of a neuropeptide that resembles dynorphin A9 and whose amino acid sequence is Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln. The rat-brain cDNA encodes the peptide flanked by Lys-Arg proteolytic cleavage motifs. The synthetic heptadecapeptide potently inhibits adenylate cyclase in CHO(ORL1+) cells in culture and induces hyperalgesia when administered intracerebroventricularly to mice. Taken together, these data indicate that the newly discovered heptadecapeptide is an endogenous agonist of the ORL1 receptor and that it may be endowed with pro-nociceptive properties.

The Therapeutic Potential of Nociceptin/Orphanin FQ Receptor Agonists as Analgesics without Abuse Liability

“…58,59 Due to its widespread locations, NOP receptor may participate in a broad range of physiological and behavioral functions producing pleiotropic effects. 58−60 Like most of classical opioids, nociceptin/orphanin FQ (N/ OFQ), a heptadecapeptide that is an endogenous ligand for the NOP receptor, inhibits cyclic AMP accumulation, 61,62 inhibits Ca 2+ entry, 61 and increases K + conductance in neurons. 63,64 These actions result in a decreased neuronal excitability and neurotransmitter release.…”

Neuropeptidomics: MS Applied to the Discovery of Novel Peptides from the Brain

“…The subtractive hybridization approach was used to discover the hypocretins and orexins, which are peptides that regulate feeding and wakefulness behavior (17 ). Orphan G-protein-coupled receptors (GPCRs) have been used as targets to identify and isolate their endogenous ligands, for example, nociceptin, the natural ligand for the opioid-like receptor (18,19).…”

The Mouse Defense Test Battery: pharmacological and behavioral assays for anxiety and panic

“…The heptadecapeptide nociceptin/orphanin FQ is a recently discovered neuropeptide that exhibits structural homology with the opioid peptides and binds to an opioid-like G protein-coupled receptor (called OP 4 ) (Calo et al, 2000b;Meunier et al, 1995;Reinscheid et al, 1995). The neuroanatomical distribution of nociceptin/orphanin FQ and its receptor in brain areas known to play a role in the modulation of emotional processes (Anton et al, 1996) has led several groups to investigate the effects of central administration of nociceptin/orphanin FQ in anxiety models.…”