One of the greatest challenges facing science today is understanding the physical basis of thought. The brain is a physical entity filled with cells that interact chemically via biochemical pathways. Research during the past fifty years has made considerable progress in understanding the scientific basis for the brain activity--understanding the biochemistry of the brain. But why certain compounds produce feelings, thoughts, and memories is still an area of exploration and research.
Narcotics are a class of compounds that affect the physical brain but also alter the mind. Specifically, they are compounds that produce narcosis or general anesthesia and relief from pain or analgesia. They alter the minds perception of pain through the actions of the brain but they also induce a sense of euphoria and well-being that has not yet been tied to specific biochemical reactions. That is, the brain is the physical entity that is composed of the neurons in our skulls. The actions of narcotics on the brain are reasonably well understood with respect to their anesthetic and analgesic properties. The mind, on the other hand, is our self --our thoughts and feelings and such--and the effects of narcotics on the mind are less clear, particularly with respect to the sense of euphoria and tranquility that the compounds induce.
Many different pharmaceutical agents are narcotics. However, in legal terms in the United States, only those compounds that are also addictive are defined as "narcotics". Their use is carefully regulated or prescribed and a significant amount of energy and money has been spent dealing with illegal narcotics. The use of legal narcotics is regulated through the medical community.
The resinous juices from the seed casing of the opium poppy (Papaver somniferum) are the source of naturally occurring narcotics. This material is a complex mixture of about 20 different alkaloids or nitrogen containing organic bases. The principal alkaloid, morphine, on makes up about 10% of this mixture. Other compounds, such as codeine, can be found within this collection of alkaloids.
Historically, opium has been one of the most important medicines because of its narcotic effects. The Greek physician Galen (c.130-c.200), administered opium juice as a calming agent for asthmatics, to relieve the pain of headaches, gallbladder infections, colic, and kidney stones, and for the treatment of congestive heart failure. But the psychoactive effects of opium have probably been used for even longer and opium probably only takes a back seat to alcohol as the most common drug used by humanity. Certainly, writings from ancient Sumeria dated to 4000 B.C. seem to describe the euphoric effects of opium. The ancient Greeks appear to have used opium "recreationally" as well as a medicine. The plant-derived drug called "nepenthe", described by Homer in the Odyssey was most likely opium as the symptoms are consistent. The importance of opium in Roman culture is evident by the fact that Somnus, the Roman god of sleep, is frequently depicted with opium poppies or a container filled with opium. Sleep, a sense of well being, and mild euphoria were the characteristics of opium.
This idyllic view of opium juice persisted well into the nineteenth century. Opium dens were an established part of society and many of the English romantic writers, for example, were frequent users. Samuel Taylor Coleridge's (1774-1834) well known poem, Kubla Khan was a result of an vision he experienced under the influence of opium. Thomas De Quincey (1785-1859) and Elizabeth Barrett Browning (1806-1861) were also users, despite an increasing awareness of the potential for addiction.
Admittedly, though, because the extract from the opium poppy contains a mixture of compounds and is diluted by sugars, water, and other phytochemicals, it is not nearly as addictive as the pure compounds. In 1805, a young German chemist, Friedrich Sertürner (1783-1841) was able to extract the psychoactive substance from opium poppies and demonstrate its efficacy. He named the substance "morphine" after Morpheus, the Greek god of dreams and visions. The actual isolation of morphine had one intellectually important side effect. It induced other chemists to search for and extract the active components from other medicinal plants, such as salicylic acid from willow bark which, when acetylated, is "aspirin".
As long as opium was in the form of a plant extract, it could only be administered orally and this hid much of its addictive properties. The pure compound, morphine, could be diluted in water and, with the invention of the hypodermic syringe in 1853, injection directly into the blood stream became the favored method of delivery. This both intensified the psychoactive properties of the compound and increased the speed with which they were realized. The analgesic and anesthetic properties aided in surgery and recovery by allowing for pain management. Both the American Civil War and the Franco-Prussian War saw the widespread use and overuse of morphine. Addiction to morphine was labeled "the soldier's disease". The fact that morphine also induced constipation meant that it was applied as a treatment for dysentery, another common complaint amongst soldiers.
With the realization of the addictive potential of morphine, chemists began to investigate possible alternatives. Methylation of the two alcohol groups on the morphine molecule produced codeine, which was not as addictive but also not as effective. Acetylation, similar to the acetylation of salicylic acid, increased the potency of morphine by making the compound more soluble in brain fat and facilitating transfer across the blood brain barrier. This new compound, heroin, was a much better analgesic and was advertised as being non-addictive. Indeed, as late as 1900, it was thought to be a "safe" drug. Many cough syrups and other over-the-counter drugs contained heroin as their active principle. Of course, with the benefit of history, we now know of the damaging effects of heroin and other narcotics. The societal cost, in both monetary terms and human potential, is enormous. Still, researchers have yet to find a better drug for controlling pain and this has lead to calls for its use in the treatment of terminal cancer patients and others suffering from severe pain.
The question of how narcotics act— what it is that they do in the brain that so profoundly affects the mind-- has, for the most part, been solved. The story begins with the isolation of neuroreceptors specific for the opiates by Solomon Snyder and co-workers in 1973. They achieved this by using a combination of "agonists", which are compounds that act at a receptor site to generate some measurable change in body function, and "antagonists", which act to inhibit agonists. By selective filtration of neuronal membranes and radioisotope labeling, they were able to show that specific neuroreceptors are sensitive to the opiates. Further identification of the location of the neuroreceptors within the brain, via thin tissue slicing, showed that the opiates act to block pain in the brain stem. The sense of euphoria may be tied to the abundance of receptors within the limbic system which is the part of the brain that is thought to be related to emotions.
Of course, finding very specific opiate receptors in the brain begs the question of why they are there. We did not evolve to eat poppies and yet one in every million receptor sites seems to be ideally suited to binding compounds from them. Scientists quickly realized that there must be naturally occurring compounds that acted like the opiates. They termed these compounds "endorphins", short for endogenous morphines. In Scotland, John Hughes and Hans Kosterlitz took advantage of the ability of opiates to induce intestinal contractions to test for the naturally occurring analogues. By the end of 1975, they had succeeded in finding two short peptide chains, made up of five amino acids that differed in only the terminal amino acid, that appeared to fill the natural role of the opiates. These were the body's own narcotics, designed to intercept and reduce the sensation of pain. They named their new discovered compounds "enkephalins", a term derived from Greek for "in the head", and this has lead to confusion every since. Strictly speaking, the enkephalins are the two amino acid sequences discovered by Hughes and Kosterlitz. The term endorphins is reserved for the larger class of natural opiates of which several other examples have been discovered.
The actual binding site of the narcotics, both natural and plant derived, has been deduced from the common morphology of the morphine family of compounds and the amino acid sequence. The tyrosine residue in the amino acid along with the peptide chain bind to a specific receptor site using a combination of Van der Waals interaction and hydrogenbonding. This understanding has aided in the development and synthesis of analogues for morphine. Unfortunately, potency with regard to analgesic and anesthetic properties and an addictive potential seem to be tied together. Still, this understanding has lead to new drugs such as Naloxone which is a potent opiate antagonist. Indeed, heroin patients suffering from massive overdoses can be "cured" in a matter of moments through the injection of Naloxone. But while it treats the immediate systems, it does nothing for the underlying psychological causes of the addiction.
And it is the addiction of both the mind and the brain to narcotics that has lead to their widespread use and abuse. Considering the social costs, these compounds have come with a high price tag.
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