Nociceptin receptor

The nociceptin receptor (NOP)_, also known as the nociceptin/orphanin FQ (N/OFQ) receptor or kappa-type 3 opioid receptor, is a protein that in humans is encoded by the OPRL1 (opioid receptor-like 1) gene. The nociceptin receptor is a member of the opioid subfamily of G protein-coupled receptors whose natural ligand is the 17 amino acid neuropeptide known as nociceptin (N/OFQ). This receptor is involved in the regulation of numerous brain activities, particularly instinctive and emotional behaviors.

Although NOP shares high sequence identity (~60%) with the ‘classical’ opioid receptors μ-OR (MOR), κ-OR (KOR), and δ-OR (DOR), it possesses little or no affinity for opioid peptides or morphine-like compounds. Likewise, classical opioid receptors possess little affinity towards NOP’s endogenous ligand nociceptin, which is structurally related to dynorphin A.

Mechanism

Nociceptin is thought to be an endogenous antagonist of dopamine transport that may act either directly on dopamine or by inhibiting GABA to affect dopamine levels. Within the central nervous system its action can be either similar or opposite to those of opioids depending on their location. It controls a wide range of biological functions ranging from nociception to food intake, from memory processes to cardiovascular and renal functions, from spontaneous locomotor activity to gastrointestinal motility, from anxiety to the control of neurotransmitter release at peripheral and central sites.

Ligands

Several commonly used opioid drugs including etorphine and buprenorphine have been demonstrated to bind to nociceptin receptors, but this binding is relatively insignificant compared to their activity at other opioid receptors in the acute setting (however the non-analgesic NOPr antagonist SB-612,111 was demonstrated to potentiate the therapeutic benefits of morphine). Chronic administration of nociceptin receptor agonists results in an attentuation of the analgesic and anti-allodynic effects of opiates; this mechanism inhibits the action of endogenous opioids as well, resulting in an increase in pain severity, depression, and both physical and psychological opiate dependence following chronic NOPr agonist administration. Administration of the NOPr antagonist SB-612,111 has been shown to inhibit this process. More recently a range of selective ligands for NOP have been developed, which show little or no affinity to other opioid receptors and so allow NOP-mediated responses to be studied in isolation.

Agonists

• Buprenorphine (partial agonist, not selective for NOP, also partial agonist of µ-opioid and δ-opioid receptors, and competitive antagonist of κ-opioid receptors)
• Cebranopadol (full agonist at NOP, μ-opioid and δ-opioid receptors, partial agonist at κ-opioid receptor)
• Etorphine
• MCOPPB (full agonist, CAS# 1028969-49-4)
• MT-7716
• Nociceptin
• Norbuprenorphine (full agonist; non-selective (also full agonist at the MOR and DOR and partial agonist at the KOR); peripherally-selective)
• NNC 63-0532
• Ro64-6198
• Ro65-6570
• SCH-221,510
• SR-8993
• SR-16435 (mixed MOR / NOP partial agonist)
• TH-030418

Antagonists

• AT-076 (non-selective)
• JTC-801
• J-113,397
• LY-2940094
• SB-612,111
• SR-16430
• Thienorphine

Applications

NOP agonists are being studied as treatments for heart failure and migraine while nociceptin antagonists such as JTC-801 may have analgesic and antidepressant qualities.

External links

• nociceptin receptor at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.