Opioids have been the mainstay of pain treatment for thousands of years, and they remain so today. Opioids such as heroin and morphine exert their effects by mimicking naturally occurring substances, called endogenous opioid peptides or endorphins. Much now is known about the basic biology of the endogenous opioid system and its molecular and biochemical complexity, widespread anatomy, and diversity. The diverse functions of this system include the best known sensory role, prominent in inhibiting responses to painful stimuli; a modulatory role in gastrointestinal, endocrine, and autonomic functions; an emotional role, evident in the powerful rewarding and addicting properties of opioids; and a cognitive role in the modulation of learning and memory. The endogenous opioid system is complex and subtle, with a great diversity in endogenous ligands (more than a dozen) yet with only four major receptor types. This chapter presents key facts about the biochemical and functional nature of the opioid system that then are used to understand the actions of clinically used opioid drugs and strategies for pain treatment.


The term opioid refers broadly to all compounds related to opium. The word opium is derived from opos, the Greek word for “juice,” the drug being derived from the juice of the opium poppy, Papaver somniferum. Opiates are drugs derived from opium, and they include the natural products morphine, codeine, and thebaine, and many semisynthetic derivatives. Endogenous opioid peptides are the naturally occurring ligands for opioid receptors. The term endorphin is used synonymously with endogenous opioid peptides but also refers to a specific endogenous opioid, b-endorphin. The term narcotic was derived from the Greek word for “stupor.” At one time, the term referred to any drug that induced sleep, but then it became associated with opioids. It often is used in a legal context to refer to a variety of substances with abuse or addictive potential.


The first undisputed reference to opium is found in the writings of Theophrastus in the third century B.C. Arab physicians were well versed in the uses of opium; Arab traders introduced the drug to the Orient, where it was employed mainly for the control of dysenteries. During the Middle Ages, many of the uses of opium were appreciated. In 1680, Sydenham wrote: “Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium.”

Opium contains more than 20 distinct alkaloids. In 1806, Serturner reported the isolation of a pure substance in opium that he named morphine, after Morpheus, the Greek god of dreams. The discovery of other alkaloids in opium quickly followed┬żcodeine by Robiquet in 1832 and papaverine by Merck in 1848. By the middle of the nineteenth century, the use of pure alkaloids in place of crude opium preparations began to spread throughout the medical world.

In addition to the remarkable beneficial effects of opioids, the toxic side effects and addictive potential of these drugs also have been known for centuries. These problems stimulated a search for potent synthetic opioid analgesics free of addictive potential and other side effects. Unfortunately, all synthetic compounds that have been introduced into clinical use share the liabilities of classical opioids. However, the search for new opioid agonists led to the synthesis of opioid antagonists and compounds with mixed agonist-antagonist properties, which expanded therapeutic options and provided important tools for exploring mechanisms of opioid actions.

Until the early 1970s, the endogenous opioid system was totally unknown. The actions of morphine, heroin, and other opioids as antinociceptive and addictive agents, while well described, typically were studied in the context of interactions with other neurotransmitter systems, such as monoaminergic and cholinergic. Some investigators suggested the existence of a specific opioid receptor because of the unique structural requirements of opiate ligands, but the presence of an opiate-like system in the brain remained unproven. A particularly misleading observation was that the administration of the opioid antagonist naloxone to a normal animal produced little effect, although the drug was effective in reversing or preventing the effects of exogenous opiates. The first physiological evidence suggesting an endogenous opioid system was the demonstration that analgesia produced by electrical stimulation of certain brain regions was reversed by naloxone (Akil et al., 1972, 1976). Pharmacological evidence for an opiate receptor also was building. In 1973, investigators in three laboratories demonstrated opiate-binding sites in the brain (Pert and Snyder, 1973; Simon et al., 1973; Terenius, 1973). This was the first use of radioligand-binding assays to demonstrate the presence of membrane-associated neurotransmitter receptors in the brain.

Stimulation-produced analgesia, its naloxone reversibility, and the discovery of opioid receptors strongly pointed to the existence of endogenous opioids. In 1975, Hughes and associates identified an endogenous opiate-like factor that they called enkephalin (from the head). Soon after, two more classes of endogenous opioid peptides were isolated, the dynorphins and endorphins. Details of these discoveries and the unique properties of the opioid peptides have been reviewed (Akil et al., 1984).

Given the large number of endogenous ligands, it was not surprising that multiple classes of opioid receptors also were found. The concept of opioid receptor multiplicity arose shortly after the initial demonstration of opiate-binding sites. Based on in vivo studies in dogs, Martin and colleagues postulated the existence of multiple types of opiate receptors (Martin et al., 1976). Receptor-binding studies and subsequent cloning confirmed the existence of three main receptor types: m, d, and k. A fourth member of the opioid peptide receptor family, the nociceptin/orphanin FQ (N/OFQ) receptor, was cloned in 1994. This latter receptor is not, strictly speaking, opioid in its function, in that it does not interact with any of the classical opiate ligands, but it is part of the opioid family based on extensive sequence homology. In addition to these four major receptor classes, a number of subtypes have been proposed, such as e, often based on bioassays from different species (Schulz et al., 1979), i (Oka, 1980), l (Grevel and Sadee, 1983), and z (Zagon et al., 1989). In 2000, the Committee on Receptor Nomenclature and Drug Classification of the International Union of Pharmacology adopted the terms MOP, DOP, and KOP to indicate m, d, and k opioid peptide receptors, respectively. The committee also recommended the term NOP for the N/OFQ receptor.


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