Opioid receptors

Opium and its derivatives have been used for centuries; findings of fossilized opium poppy seeds dating as far back as 30 000 yr suggest the use of opium by Neanderthal man. In 1799, Friedrich Serturner discovered the major active ingredient of opium, which he named morphine and opioid pharmacology was born. Morphine and other opioid drugs act on an endogenous opioidergic system which is not only involved in setting pain (nociceptive) threshold and controlling nociceptive processing but also participates in modulation of gastrointestinal (GI) function, endocrine and autonomic function, and a possible role in cognition. Evidence for the existence of multiple opioid receptor types was reported based on the different anatomical location and the pharmacological profiles of compounds that were eventually used to name them, that is, morphine (mu), ketocyclazocine (kappa), and vas deferens (delta). In subsequent years, the molecular cloning, functional expression, and characterization of these receptors has been reported and it is understood that each receptor is the product of a single gene; OPRM1 (m), OPRK1 (k), and OPRD1 (d). The nociceptin orphanin FQ peptide receptor was first reported as an opioid receptor-related clone, formerly named LC132 or ORL-1, and with no known endogenous ligand, the receptor was dubbed ‘orphan’. 2 Its orphan status remained until the formal identification of an endogenous ligand, nociceptin/orphanin FQ (N/OFQ), isolated from brain extracts, utilizing a process known as reverse pharmacology (the searching of a drug to activate a molecular cloned receptor), simultaneously by Meunier and colleagues and Reinscheid and colleagues. The International Union of Basic and Clinical Pharmacology (IUPHAR) nomenclature regards MOP (m), KOP (k), and DOP (d) as ‘classical’ opioid receptors, a distinction based on the sensitivity to the opioid antagonist naloxone. Nociceptin receptor (NOP) is used for the N/OFQ peptide receptor which is currently classified as a nonopioid member of the opioid receptor family, based on similarities in structure and localization to the classical opioid receptors but insensitivity to naloxone. Putative subtypes of the classical opioid receptors have been suggested, m1, 2, and 3 for MOP, d1 and 2 for DOP, and k1a, 1b, 2a, 2b, and 3 for KOP, based on a variety of evidence such as the differential modulation by drugs on functional responses in vivo and in vitro, along with incomplete tolerance of functional responses seen when using different drugs targeting the same receptor. However, the legitimacy of these pharmacologically defined subtypes is deficient when placed alongside the molecular research which reveals how individual opioid receptors are encoded by a single respective gene, and that the knock-out of a single receptor gene leads to the loss of all functionality associated with the receptor. Pharmacologically defined subtypes of receptor are the consequence of a number of processes including alternative splicing of opioid receptor genes. To understand the process of alternative splicing, and how it may result in different subtypes of receptor, it is necessary to understand how opioid receptor genes are encoded in genomic DNA which consists of introns and exons. Introns represent nucleotide sequences encoded by the gene that are removed in the formation of RNAs, while exons represent nucleotide sequence encoded by the gene that remains in the final RNA. In the case of opioid receptors, gene splicing removes the intron sequences leaving a messenger RNA that is translated into the final protein structure of the receptor. Alternative splicing concerns how, in this process, after the removal of the introns, the exons can be reattached in different ways resulting in different RNAs and therefore leading to different opioid receptor proteins, that is, opioid receptor subtypes.