A Brief History of Opiates, Opioid Peptides, and Opioid Receptors Michael J
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Proc. Natl. Acad. Sci. USA Vol. 90, pp. 5391-5393, June 1993 Review A brief history of opiates, opioid peptides, and opioid receptors Michael J. Brownstein Laboratory of Cell Biology, National Institute of Mental Health, Bethesda, MD 20892 "Presently she cast a drug into the sick and gods of death as well. It was pheus. (Codeine was isolated from opium wine ofwhich they drank to lull all pain given along with hemlock to put people a few years later.) Pure morphine, a weak and anger and bring forgetfulness of quickly and painlessly to death, and it base or alkaloid, the structure ofwhich is every sorrow." came to be used medicinally. The Ebers shown in Fig. 1, could be made in large The Odyssey, Homer Papyrus (ca. 1500 B.C.), for example, amounts. After the invention of the hy- (Ninth century B.C.) includes the following description of a pordermic syringe and hollow needle in "remedy to prevent excessive crying of the 1850s, morphine began to be used for It is hard to decide when and where the children" (see ref. 2, p. 35): "Spenn, the minor surgical procedures, for postoper- opium poppy was first cultivated. It may grains of the spenn (poppy)-plant, with ative and chronic pain, and as an adjunct have been grown for its seeds before excretions of flies found on the wall, to general anesthetics. In fact, it was people discovered how to prepare meko- strained to a pulp, passed through a sieve Claude Bernard who first investigated nion from the leaves and fruits of the and administered on four successive the use of morphine for premedicating plant or opium (from "opos," the Greek days. The crying will stop at once." This experimental animals. He found that it word for juice) from the liquid that ap- remedy and others containing opium reduced the amount of chloroform pears on the unripe seed capsule when it (such as spongia somnifera, sponges needed to produce anesthesia. is notched. soaked in opium used to relieve pain Unfortunately, morphine had just as The use of written records to decipher during surgery) were dangerous because much potential for abuse as opium and the early history of opium use and abuse they varied in potency and rate of absor- was not terribly safe to use either. Con- is hard because descriptions of drugs by bance. Consequently, many physicians sequently, a great deal of energy was ancient authors are often ambiguous. The were wary of using them. spent trying to develop a safer, more preparation described by Homer-given Most authors* agree that, as early as efficacious, nonaddicting opiate. In 1898, by Helen, the daughter of Zeus, to the eighth century A.D., Arab traders heroin was synthesized and pronounced Telemachus and his friends to help them brought opium to India (6) and China (7) to be more potent than morphine and free forget their grief over Odysseus' ab- and that between the tenth and thirteenth from abuse liability. This was the first of sence-was attributed to Homer's imag- centuries opium made its way from Asia several such claims for novel opiates. To ination by Theophrastus (300 B.C.) who Minor to all parts of Europe. With the date, none has proven valid. was himself aware of the method used to drug came addiction. Starting in the six- In 1939, the search for a synthetic produce opium. Other writers (e.g., Dis- teenth century, manuscripts can be found substitute for atropine culminated seren- kourides, A.D. 60) have argued that the describing drug abuse and tolerance in dipitously in the discovery of meperidine drug alluded to by Homer contained hen- Turkey, Egypt, Germany, and England. (10), the first opiate with a structure bane, the active ingredient of which is Nowhere was the problem of addiction altogether different from that of mor- scopolamine. Most modem pharmacolo- greater than in China where the practice phine. This was followed in 1946 by the gists including Schmiedeberg (1) and of smoking opium began in the mid- synthesis of methadone (11), another Lewin (2) feel that Helen administered seventeenth century after tobacco smok- structurally unrelated compound with opium to the men. Indeed, Kritikos and ing was banned. Efforts to suppress the pharmacological properties similar to Papadaki (3) have suggested that Telema- sale and use of opium failed because the those of morphine. The abstinence syn- chus may not have experienced any of British, laterjoined by the French, forced drome seen when methadone consump- the toxic effects ofopium because he and the Chinese to permit opium trade and tion ceases is different from that of the his contemporaries used it habitually. consumption. natural alkaloid. Its onset is slower, it Despite difficulties in interpreting an- In 1806, Serturmer (8, 9) isolated the lasts longer, and it is less intense. Fur- cient writings and archeological data, a active ingredient in opium and named it thermore, it is orally active. Therefore, it picture of opium use in antiquity does morphine after the god of dreams, Mor- is given to human addicts by clinicians as emerge from them. There is general a substitute for morphine. Stable metha- agreement that the Sumerians, who in- *The Arabian system of medicine, including done addicts can lead reasonably normal habited what is today Iraq, cultivated the use of opium, was introduced into India lives, and the drug can gradually be with- poppies and isolated opium from their by Muslims in the ninth century A.D. The drawn when they no longer desire to use seed capsules at the end of the third Greeks, however, were using Indian drugs by it. millenium B.C. They called opium "gil," the third century B.C., and conversely, In 1942, Weijlard and Erikson (12) pro- the word forjoy, and the poppy "hul gil," opium seems to have been employed in In- dian folk remedies in the same period. As for duced nalorphine (N-allylnormorphine), plant ofjoy. It appears that opium spread China, opium was mentioned in the medical the first opiate antagonist (13). This com- from Sumeria to the remainder of the old book K'ai-pao-pen-tsdo in A.D. 973. The pound could reverse the respiratory de- world. recent discovery of silk in the hair of a tenth pression produced by morphine and pre- At first opium may have been em- century B.C. Egyptian mummy (5) indicates cipitate the abstinence syndrome in ad- ployed as a euphoriant in religious ritu- that there may have been regular traffic on dicts. In spite of the fact that the "Silk Road" in ancient times. One might nalorphine als, taken by mouth or inhaled from infer from the above that opium was known, counters the actions of morphine, it is heated vessels (4). Knowledge of its use if not widely used, on both the Indian sub- effective as an analgesic agent. This is may initially have been confined to continent and in Asia well before the eighth because it is a mixed agonist-antagonist. priests representing gods who healed the century A.D. Its utility as a pain killer is limited since 5391 Downloaded by guest on September 28, 2021 5392 Review: Brownstein Proc. Natl. Acad. Sci. USA 90 (1993) HO Another group of peptides structurally ties of several opiate compounds and related to the enkephalins were identified looked for "cross tolerance" among the in 1981 (22). The first ofthese was named opiates as well (i.e., the ability of a drug dynorphin. Finally, a fourth family of to prevent withdrawal symptoms -after opioid peptides was shown to be present removal of a second drug from an animal 0 in the skin of the frog Phyllomedusa tolerant to it). The results ofthese exper- bicolor (23). These peptides, now known iments suggested the existence of three collectively as deltorphins, are quite un- types of receptors named after the drugs N -CH3 usual; they contain D-amino acids. The used in the studies: ,u (morphine), K (ke- first such species characterized had the tocyclazocine), and oa (SKF 10,047 or The crreceptor is HO sequence Tyr-D-Met-Phe-His-Leu-Met- N-allylnormetazocine). Asp-NH2. now generally thought not to be an opioid FIG. 1. Morphine (pKb = 6.13). Heroin, Not unexpectedly, each of the opioid receptor. diacetylmorphine, is more lipid soluble than peptides is made as part of a larger pre- After they discovered the enkephalins, morphine and enters the brain more readily. cursor protein. In mammals there are Kosterlitz and his colleagues (30) wanted Heroin is converted to 6-monoacetylmorphine three such precursors-proenkephalin to know which receptor(s) they act on. and morphine, which are responsible for its (24), prodynorphin (25), and proopiomel- They found that morphine was more ef- actions on central peripheral targets. anocortin (26). Proenkephalin gives rise fective than the enkephalins in inhibiting to four Met-enkephalins, one Leu- electrically induced contractions of the it often produces anxiety and dysphoria, enkephalin, one Met-enkephalin-Arg6- guinea pig ileum. Surprisingly, the pep- but its discovery led to the development Phe7, and one Met-enkephalin-Arg6- tides were more active than morphine in of additional compounds, such as nalox- Gly7-Leu8. Additional larger fragments of inhibiting contraction of the mouse vas one, that are relatively pure opiate an- proenkephalin have been isolated from defferens. Furthermore, the action of en- tagonists. tissues. These may be incompletely pro- kephalins on the vas deferens was com- By the mid-1960s, it was becoming cessed or, possibly, opioid ligands in paratively insensitive to naloxone. Based clear that the actions of opiate agonists, their own right. on these observations, Kosterlitz and his antagonists, and mixed agonist-antago- Prodynorphin also gives rise to several colleagues (30) proposed that a fourth nists could best be explained by actions biologically active peptides all of which type of opioid receptor, the 8 receptor, on multiple opiate receptors.