Nociceptin receptor (OPRL1) (NOP)

The Nociceptin receptor (NOP), also known as Opioid receptor-like 1 (ORL-1), is a G protein-coupled receptor (GPCR) that is structurally related to classical opioid receptors but distinct in its ligand binding profile (UniProt P41146). It is primarily activated by the endogenous neuropeptide nociceptin/orphanin FQ (N/OFQ) and plays a critical role in modulating pain, stress, anxiety, and reward pathways within the central nervous system (IUPHAR/BPS Guide to Pharmacology). The receptor is a significant therapeutic target for conditions such as chronic pain, depression, and substance use disorders, as its activation can produce both analgesic and anti-analgesic effects depending on the physiological context and dosage (PubMed: 25333798). Buprenorphine, a widely used analgesic and opioid use disorder treatment, acts as a partial agonist at the NOP receptor, while its metabolite norbuprenorphine is a potent NOP agonist; however, the metabolite buprenorphine-3-glucuronide is generally considered pharmacologically inactive at this site (PubMed: 22107012). Targeting the NOP receptor is of particular interest in drug development to create multi-functional ligands that provide pain relief with reduced risks of respiratory depression and addiction compared to traditional mu-opioid agonists (PubMed: 30139915).

Other names

Opioid receptor-like 1ORL1OPRL1Nociceptin/orphanin FQ receptorKappa-type 3 opioid receptorLC132

Agonism or antagonism of the NOP receptor modulates Gi/o protein signaling, leading to the inhibition of adenylyl cyclase, reduction of cAMP levels, and regulation of ion channel activity (e.g., activation of K+ channels and inhibition of Ca2+ channels) to alter neuronal excitability.