Introduction
The term “endorphin” means “endogenous, morphine-like substance.” These naturally produced chemicals were discovered after researchers in the 1970s found that the opiate drugs morphine and heroin could physically bind to brain tissue. This binding occurred at neurochemical receptor sites on certain brain cells. Researchers began looking for the chemical that normally used these receptor sites, and soon discovered endorphins and their sister chemicals, the enkephalins. Collectively, these chemicals are referred to as endogenous opioids (opioid means opium-like). All are peptides, which consist of at least two amino acids linked together, and are often called opiate peptides. (Note that proteins, the body’s building blocks, consist of multiple peptides.) Some endogenous opioids function as neurotransmitters for communication between brain cells. Others function less for the communication of a specific message and more as modulators of a neuron’s response to yet other neurotransmitters.
The endorphins and other opioids are important because of their role in controlling pain, which has long been of interest to the medical profession.
Morphine, which chemically resembles the endorphins, was one of the first painkillers known to humankind. It is the active component of opium, and its effects have been recognized for centuries. Morphine is still widely used clinically for treating pain. Unfortunately, morphine is addictive and produces unpleasant withdrawal symptoms. Also, the body develops a tolerance to morphine so that ever-increasing doses are needed to control pain. Many other effective pain relievers have similar problems. The discovery of endorphins and enkephalins has provided hope that scientists will one day be able to control pain without fear of addiction or withdrawal symptoms after the treatment with the painkiller ends.
Beta Endorphins, Enkephalins, and Dynorphins
Endogenous opioids include alpha, beta, gamma, and delta endorphins; leucine and methionine enkephalin; dynorphins; and endomorphins. Most of these interact with three major subtypes of opioid receptors: mu, delta, and kappa. Of the endogenous opioids themselves, the beta-endorphins, the enkephalins, and the dynorphins have been most widely studied. The endorphins are the largest molecules in the endogenous opioid family, at about thirty amino acids long, while the enkephalins are shortest at about five amino acids long. Beta-endorphin and the dynorphins are more potent than the enkephalins and last longer in the body. Enkephalins are typically neurotransmitters, substances released by neurons that cause another nerve, muscle, or gland to respond to a given stimulus, of the brain and spinal cord. Though, weaker than endorphins, enkephalins are still considerably stronger and longer lasting than morphine.
The three primary types of endogenous opioids are distributed somewhat differently in the brain and spinal cord. The enkephalins and dynorphins are found primarily in the dorsal horn of the spinal cord, which receives incoming information, such as pain, from the body, and in the periaqueductal gray matter, which is part of the midbrain. Activation of the periaqueductal gray matter is clearly associated with analgesia for pain without affecting the person’s response to other touch-related sensations such as pressure and temperature. This area receives input from the frontal lobe, amygdala, and hypothalamus, structures involved in emotional expression, and projects to circuits in the brainstem that are involved with pain regulation. The periaqueductal gray matter also plays a role in species-specific behaviors such as predation and self-defense. Beta-endorphin is found most commonly in the hypothalamus, which projects to many other areas of the brain, including areas where enkephalins and dynorphins are found. Beta-endorphins in the brain are released in response to unpleasant stimuli entering the brain. In the spinal cord, they are released in response to impulses relayed from the brain to peripheral muscles.
The most widely studied effect of endogenous opioids such as the endorphins is their ability to block painful stimuli (the analgesic effect). However, they have been associated with many other physiological activities, including thermoregulation, appetite, emotion, memory, lipolysis, regulation of bowel movements, reproduction, and pleasurable experiences. They produce their effects by binding to target cells at receptor sites, which are protein structures of a particular size, shape, and chemical charge that can be activated only by specific chemicals. The receptor sites for the opioid peptides are the same ones that bind morphine, which allows the drug to produce effects similar to those produced by endogenous opioids.
Mechanism and Effects
The endorphins and other endogenous opioids appear to be inhibitory in nature. Activation of the opioid system increases inhibition in brain areas such as the periaqueductal gray matter, which in turn decreases the input the brain receives from the peripheral nervous system and the spinal cord. Thus, painful stimuli are blocked from reaching the upper brain. Morphine works the same way.
Although their effects are powerful, the endorphins and other endogenous opioids are typically found only in very low concentrations in nervous tissue. Because of this, most opioid research has been conducted in animals, in which cellular effects and injections into specific cells can be achieved. Animals, however, are unable to describe any feelings that might be produced. In humans, endorphins have generally been studied through plasma levels or cerebrospinal fluid levels.
Endorphins and other endogenous opioids are released in humans under conditions of physical or psychological stress. The physical stress most closely associated with an increase in plasma endorphin levels is aerobic exercise, especially running, although levels typically return to normal within thirty minutes to an hour after cessation of exercise. The endorphins are generally credited with decreased sensitivity to pain in athletes who suffer physical injury. They may also explain why some runners experience a feeling of well-being after prolonged, strenuous exercise.
Addiction and the Placebo Effect
The explanation for morphine addiction may also lie with opioids like the endorphins. Because morphine and the endorphins bind to the same receptors on cell membranes, the theory suggests that morphine, when available, occupies some of the receptor sites while the endorphins occupy the rest. This shuts down pain sensitivity. However, morphine and the other opiate drugs are exogenous (from outside) substances and are not as readily available to the individual as the endogenous opioids.
Furthermore, in patients to whom morphine is supplied, the natural circulating levels of the opioid enkephalins appear to decrease. Once enkephalin levels fall, the receptor sites to which they had been bound are no longer occupied, and pain stimuli can reach the brain. The increase in pain signals individuals to seek relief, and because they cannot increase their own endogenous opioids, they may take drugs such as morphine instead. This decrease in the circulation of natural opioids after morphine treatment may explain the phenomenon of drug craving and may partially explain morphine’s withdrawal effects.
Endogenous opioids are even involved in addictions to other substances, most notably alcohol. Alcohol appears to trigger the release of endogenous opioids, which produces some of the reinforcing effects of alcohol. Plus, abstinence from alcohol increases the numbers of certain opioid receptors in a brain structure called the nucleus accumbens, which is involved in reinforcement. The increase in opioid receptors caused by alcohol abstinence is associated with an increased craving for alcohol.
Endorphins also appear to be involved in the placebo effect. Patients who receive sugar in place of typical analgesics and are told they will feel better soon, often do experience an improvement in their condition. Research shows that the improvement brought about by a placebo can sometimes be blocked by injections of naloxone, which inhibits endogenous opioids. The belief that an analgesic will work apparently triggers the release of endogenous opioids and actually produces some pain relief, at least in some individuals.
Role of Stress and Exercise
Studies show that both animals and humans become less sensitive to painful stimuli while under stress. In humans, many instances have been described in which individuals experienced the severe stress of an injury without even being aware of the injury, or, if aware, without feeling the pain. For example, wounded soldiers sometimes claim to experience no pain from serious injuries, and sometimes even feel a sense of detachment or curiosity when viewing their wounds. Similarly, people show decreased pain sensitivity when engaged in the pleasant, but physically stressful, act of sexual intercourse. Much of this analgesic effect appears to be mediated by endogenous opioid release in the brain in response to pain. Drugs that block opioid receptors in the brain generally eliminate the decrease in pain sensitivity brought on by stressful events. Psychologically, this makes good sense. Pain is a warning to stay away from dangerous stimuli, but in individuals already fighting for their lives, pain is more of a distraction than an aid. For sexual intercourse, some experience of pain often occurs with the pleasure, but a species would not survive if the pain overcomes the reproductive drive.
Mood also can apparently be influenced by levels of endogenous opioids in the brain. Some badly injured people describe their mood as serene and accepting of the situation. More common experiences can alter mood in similar ways. One example is the athlete doing aerobic exercise. Strenuous exercise leads to physiological changes very similar to a stress reaction. Intense exercise, like that seen in long-distance running, can induce increases in naturally occurring opioids. Runners tested after a long run typically show elevated endorphin levels. Not only do they experience less pain, which is almost certainly an endorphin effect, but they sometimes experience a feeling of elation called the runner’s high.
Some scientists attribute the runner’s high to elevated endorphin levels. However, although endorphin levels remain elevated for only thirty minutes after a long run, the runner’s mood typically remains positive for far longer, indicating that factors other than endorphins, such as other brain chemicals and the psychological sense of accomplishment, probably play a role. Still, dedicated runners and others who regularly do aerobic exercise often describe a sense of loss when unable to run or exercise. Some researchers have suggested that this need to exercise resembles a form of exercise addiction and that the sense of loss can be seen as withdrawal from the person’s own endorphins. Exercise has even proven successful as a treatment for mildly depressed individuals, although whether this effect involves the endogenous opioids is unclear.
Animal Research
The best known effects of the endogenous opioids are their ability to induce analgesia and to reinforce behavior. However, other effects have also been observed. Many of these have been seen primarily in animals, and have not been clearly identified in humans. For example, rats injected with endogenous opioids during memory tasks generally show impaired performance. Rats show increased physical activity with low doses of endorphins but generally show decreased activity with higher doses. Rats also experience increased grooming tendencies and increased sexual arousal after treatment with opiate peptides, and the suckling behavior of rat pups is associated with elevated opioid levels.
Other animals also experience changes in behavior after administration of endogenous opioids. Young chicks isolated from their mother or from other young chicks normally give loud distress cries. This behavior decreases after endorphin administration, and similar effects have been seen in guinea pigs and dogs. Goldfish show increased schooling behavior when treated with endorphins, and wild, white-crowned sparrows increase feeding behavior when given endorphin injections, which may reflect a decrease in their stress response to being captured. Undoubtedly, other behavioral effects of endogenous opioids will be identified in animals in the future, and it is likely that correlates will be found for many of these behaviors in humans.
History of Opiate Studies
During the early 1970s, the US government declared a war on drugs. Federal money was made available to study the effects of drugs and the basis of drug addiction. The opiates, particularly heroin, were included in the targeted drug groups. It was theorized at the time that if the opiates had an effect on the brain, they must be operating on receptors. Some of these opiate-like receptors were isolated in 1973 at the Johns Hopkins University School of Medicine by Solomon H. Snyder and Candace Pert. The presence of natural opioid receptors in humans suggested the existence of endogenously occurring opiate-like substances, and the first such endogenous opioids were isolated and identified in 1973. It soon became clear that the existence of endogenous opioids such as the endorphins and enkephalins would revolutionize theories about the role of natural brain chemistry in drug addiction. It was not understood until much later how many other behaviors would also involve natural brain opioids.
The endogenous opioids remain a major area of study in neuroscience. A complete understanding of such phenomena as pain, stress, eating, addiction, reinforcement, sexual pleasure, and many other behaviors will require a more complete knowledge of the endorphins, enkephalins, dynorphins, and other endogenous opiate-like substances. The promise is great for developing better pain relievers and better treatments for stress and drug addiction. It remains to be seen whether the ability of these substances to alter mood will be a danger or a boon.
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