ORL1

ORL1, also known as the opioid receptor-like 1 receptor, is a G protein-coupled receptor that belongs to the opioid receptor family but is pharmacologically distinct from the classical mu, delta, and kappa opioid receptors. It is also referred to as the nociceptin receptor or NOP receptor. The receptor is activated by nociceptin/orphanin FQ (N/OFQ), a 17-amino-acid neuropeptide derived from prepronociceptin.

In humans, ORL1 is encoded by the OPRL1 gene. The receptor has seven transmembrane domains and couples primarily to Gi/o proteins. Activation inhibits adenylyl cyclase, reduces cAMP production, and modulates ion channels, leading to decreased neurotransmitter release. This signaling pathway influences neuronal excitability and can produce various physiological effects depending on the neural circuit involved.

ORL1 is widely expressed in the central nervous system, including regions such as the periaqueductal gray, cortex, hippocampus, amygdala, and spinal dorsal horn, as well as in some peripheral tissues. Its physiological roles encompass modulation of pain, stress responses, learning and memory, feeding, mood, and reward, with implications in anxiety and addictive behaviors. The receptor also participates in immune and autonomic processes in certain contexts.

Pharmacology involves the endogenous ligand N/OFQ and a range of synthetic ligands, including peptide and non-peptide agonists and antagonists. Notable research tools include selective NOP antagonists to study function. Therapeutic interest focuses on developing ORL1 modulators as analgesics or treatments for anxiety and addiction, aiming to achieve benefits without the typical adverse effects associated with classical opioids. As of now, no ORL1-targeted drug has been approved for clinical use.