Opioid Receptors

GPCRs interacting with morphine and other analgesic opiate ligands were first defined pharmacologically in various tissues. The cloning of the m, 5, and k opioid receptors (designated MOR, DOR and KOR by International Union of Pharmacology nomenclature) in the 1990s gave real promise that selective agents with fewer side effects would be developed. Morphine is a MOR-selective ligand with very low potencies at both KOR and DOR. Overwhelming evidence, including lack of morphine-induced analgesia in MOR knockout mice153 identified the recombinant MOR protein as necessary for analgesic actions of opioid compounds.

Some aspects of the involvement of opioid receptors in analgesia, such as the significance of multiple splice variants of the MOR154 and identification and characterization of two new human m opioid receptor splice variants (hMOR-1O and hMOR-1X) remain to be clarified. Whereas selective DOR ligands have been developed with the promise of analgesia with fewer side effects155 in acute pain states, DOR antagonism demonstrates less efficacy than morphine.156 However, DOR antagonists potentiate morphine-induced analgesia when coadministered,157 158 and this effect is likely due to direct interaction of MOR and DOR proteins in hetero-oligomers.159 Indeed, MOR and DOR receptors are coexpressed in neurons of DRG and dorsal spinal cord,160 suggesting this heterodimer may be a relevant target for analgesics.

Another related receptor, opioid receptor-like 1 (ORL-1),161 was cloned based on homology with the known opioid receptors. It appears to have low affinity for most opioid ligands and high affinity for an endogenous peptide ligand, nociceptin or orphanin F/Q.162 163 As the name implies, nociceptin was first described as a peptide that induces hyperalgesia when injected into the spinal cord, suggesting this receptor may also be involved in pain modulation and represent a useful therapeutic target. However, it can act in both spinal cord and higher CNS centers to induce analgesia and hyperalgesia, respectively, further adding to the complexity of modulation within the opioid receptor family.164

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