"The first wave felt like a combination of mescaline and methedrine."
"I nodded, barely able to talk now. My body felt like I'd just been wired
into a 220 volt socket."
"It was hard to move my jaws; my tongue felt like burning magnesium. 'No
. . . nothing to worry about,' I hissed. 'Maybe if you could just . . .
shove me into the pool, or something . . . '"
"I couldn't move. Total paralysis now. Every muscle in my body was
contracted. I couldn't even move my eyeballs, much less turn my head or
talk."
--"Fear and Loathing in Las Vegas" by Hunter Thompson, 1972
The only source for the drug mentioned above are the adrenal glands from a living human body. Adrenochrome, the above drug, has potency greater than the hardest drugs we have on the street, "a combination of mescaline and methedrine" says Thompson. But is there proof that such a molecule actually exists in our bodies? Do we naturally have something addictive enough to turn the drug world upside down? Actually we do and it is better known as the endorphin.
A natural, endogenous relative of the opiate morphine, endorphin literally means "endogenous morphine." Named so because it affects the human body as morphine does, endorphins have a wide variety of effects on the human body and serve many purposes. Its main role is as a neurotransmitter and a neuromodulator, affecting the body on a physiological level and therefore on a larger behavioral level as well.
Like opiates, endorphins (also known as endogenous opioids or endogenous peptides) are known most widely for their analgesic properties. But in addition, they also serve roles in anxiety, the production of euphoria and dream like states, as well as producing a sedatory effect. As a neurotransmitter, the endorphin is crucial to the normal functioning of important processes such as motor coordination, learning and memory, gastrointestinal function, the control of seizures, and the hormonal regulation of the reproductive system (WWW 2). In the role of a neuromodulator, endorphins act as "inhibitory middlemen" in many excitatory pathways including those like acetylcholine, the catecholamines, serotonin, and substance P (a neuropeptide active in pain neurons) (WWW 3, Simon and Hiller 1994).
Among some of the endorphins' less obvious physiological effects include diuretic functions, salt and water balance, stress mechanisms and temperature control as well as its involvement in tolerance development and physical dependence. Since physiology translates into behavioral patterns, endorphins ultimately affect everyday human behaviors such as sexual behavior, feeding and drinking, grooming, locomotor and operant behavior, and memory storage and recall.
But recently the interest is not the everyday behavioral processes, but the more peculiar behaviors that humans exhibit. Within the last twenty years, an enthusiasm in the field of mental illness has emerged. Due to this curiosity, studies have since brought focus on the molecular biology of illnesses such as schizophrenia, anxiety disorders, and depression and show that endorphins could possibly serve a role in these mental disorders. Lately, it is the link between endorphins and depression that is in question and up for debate. From past results, the Endorphin-Deficiency Hypothesis for depression came about, giving a possible understanding of depression and its symptoms in terms of a deficit endorphins in the brain. But opposing evidence contradicts this hypothesis stating that perhaps it is not a lack of endorphins, but rather an excess of endorphins, or even that endorphins are not a factor in the depression question at all.
First, before an examination of the links between endorphins and depression can be made, a brief introduction to the endorphin is in order. The discovery of the first endorphin occurred very serendipitously. In 1964, Chao Hao Li, a neurochemist at the University of California in San Francisco, was investigating pituitary glands for substances that aided in the metabolism of fat. Instead of finding his desired substance, he stumbled across another amino acid substance from the camel pituitaries that he was using. Although it did not play into his questions nor his experiment, he still put the substance away in storage (WWW 1; Davis 1984). This substance was later found to be the most important endorphin in the body, beta-endorphin.
Nearly ten years later, Lars Terenius from Sweden, Candace Pert and Solomon Snyder in Baltimore, and Eric Simon from New York each independently uncovered the brain's special receptors for opiates such as morphine. Consequently these scientists wondered why human brains from around the world would have receptors for morphine, a product of flowers that originated from the Middle East. This question then spurred on the search for the endogenous chemical that corresponded to the receptors discovered (WWW 1; Davis 1984). And in 1975, the first known endogenous opioid peptide, enkephalin, meaning "in the head," was nearly simultaneously discovered by John Hughes (U of Aberdeen Scotland), Lars Terenius and Agneta Wahlstrom (U of Uppsala Sweden), and Solomon Snyder, Gavril Pasternak and Robert Goodman (Johns Hopkins U USA) (Davis 1984).
Discoveries continued in 1975 when Avram Goldstein and his associates announced the discovery of two other endogenous opioid substances while John Hughes and Hans Kosterlitz later announced that the enkephalins that they had discovered comes in two versions, methionine-enkephalin and leucine-enkephalin (Davis 1984). When Li, back in San Francisco, realized that his previously stored molecule contained the newly discovered enkephalin, he decided to inject the substance into the body. In the brain, he found that his substance was 48 more times powerful than morphine. Compounding these incredible results was the fact that it was even more addictive than morphine (WWW 1). He later called it beta-endorphin. With further research in subsequent years, researchers found that endorphins are neurotransmitters that can be found in many areas of the body including the pituitary glands, the hippocampus, pineal glands, kidneys, pancreases, the gut, and adrenal glands amongst others. Right around this same time researchers began to discover other functions of these newly discovered endorphins including its links to bodily functions and mental illnesses.
To date there are over 20 different types of endorphins for three G protein coupled receptors, mu, kappa, and delta, each named for either the prototype drugs that were used or the location where they were found (morphine, ketocyclazocine, and deferens respectively) (Simon and Hiller 1994). These 20 endogenous opioids include enkephalins, dynorphins, and a variety of other endorphins, such as beta- and alpha-endorphin. Unfortunately, it is unclear which of the 20 peptides are active at the various receptors and which are intermediates of metabolism or breakdown products (Wagner and Chavkin 1995).
Associated with this unclear existence in the body is the strange lack of a neurotransmitter reuptake mechanism for recycling of the endorphins. Because a reuptake mechanism does not exist like it does for other neurotransmitters, a new precursor must to be made every time an endorphin is needed. Consequentially it is incredibly expensive and requires a lot of energy to construct an endorphin. Due to the inefficiency of "ready to go endorphins," it is likely that endogenous peptides modulate nervous system activity over a relatively long time scale rather than in a moment to moment transfer of information (Willner 1985). Their action is also limited by their lifetime in the free state, which is in turn limited by their enzymatic degradation (WWW 3).
If these endorphins are so limited in their lifetime and function, how is it that they can be linked to long term social and behavioral processes? First let us understand why research on social and behavioral processes has been of hot interest in the last few decades. Why is it that we want to find the biological and biochemical reasons behind things in general? And why are we stretching that research and interest into personalities, behavioral processes, and such things that are not usually quantified by its molecular biology? "It is curious that the biological basis of social behaviour has been subject to relatively little scientific investigation" (Rodgers and Copper 1988).
Generally, one does not look at personality and behavioral illnesses in the light of the neurotransmitters that make up its processes. Nor does one quantify it in terms of action potentials, electrical impulses, or even the cells of the brain. A person sees the personality of another in terms of thoughts and memories, or the lack thereof. But all in all, it is the small underlying layer of biology and biochemistry that defines our personalities and the resulting biological successes and problems that we have. It goes to logic that research of the biological and biochemical processes behind mental illness should be looked at, if not extensively researched. It is therefore the goal of some scientists to determine the underlying causes of mental illness so that we may better understand them.
The search for the cause of depression begins with the observation that opioids have psychopharmacological effects in man (Almeida and Shippenberg 1991). "Because these types of psychoses tend to spontaneously fluctuate during the time course of the illness, thereby suggesting the view that the processes regulating these neurotransmitters rather than the neurotransmitters themselves, are involved in the pathogenesis of these disorders. Since endogenous opioids represent potent neurochemical regulators, modulating the activity of classical transmitters, these compounds have been the focus of many studies seeking to identify the causative factors in the initiation of these types of psychiatric diseases" (Almeida and Shippenberg 1991).
From the manic depression (bipolar disorder) model that "opioid peptides may be involved...with an excess and deficiency of opiate receptor activity being responsible for mania and depression respectively," a hypothesis that a deficiency of endorphins in depression exists is similar to that in manic depressive disorder (Judd 1978). In order to quantify the validity of this hypothesis, one must devise ways to test it first. "There are two major ways to study the link between endorphins and a general mental illness. One can either measure the levels of the particular peptide in question in the blood, the brain, or even in cerebrospinal fluid (CSF). Or one can employ pharmacological methods to either stimulate or inhibit opioid activity using antagonists such as naloxone or naltrexone" (Rodgers and Cooper 1988). Other methods to determine the link between endorphins and depression also exist, such as evaluating the possible clinical link between endogenous opioid activity and mood by examining the effects produced by the application of opiate antagonists versus that of agonists (Almeida and Shippenberg 1991). And yet another method in use is the evaluation of the possible therapeutic effects of different types of opioids in depressive syndromes (Emrich 1982).
A large debate emerges during the search for the link between endorphins and depression, with beta-endorphin being the major endogenous opioid in question. There is massive evidence in favor of the endorphin level link to depression, but there is also disputing testimony showing that changes in endorphins levels of depressed patients have not been found in clinical research.
The search for evidence began years ago with the understanding that enkephalin and opioid receptors are both localized in brain areas that are involved in mood responses (Tejedor-Real 1995). Preliminary research suggests that beta-endorphin levels in the brains of depressed patients differed from that of normal people. Whether the levels were elevated or depressed is the question. In 1977, Nathan Kline et al were the first to perform clinical trials in different types of psychiatric disorders by the use of beta-endorphin. In 1982, Risch and Brambilla et al, two different research groups, found elevated plasma levels of beta-endorphin in depressed patients, compare to normal controls (Willner 1985). After injections of beta-endorphin, they observed a general antidepressant effect (Tejedor-Real 1995). Kline furthered research by continuing beta-endorphin injection studies. Although subject to uncontrolled variables, he gave depressed people beta-endorphin and reported some temporary improvements while others even reported a state of mania with the injections (Davis 1984). In another double blind placebo controlled crossover study, 9 depressed patients showed significant improvement approximately 2 to 4 hours after beta-endorphin administration compared to the placebo. The results of this experiment suggested that depressed patients have a deficit in endorphin activity due to the improved moods with subsequent beta-endorphin injections (Li 1981).
Around the same time period, there was also research done that disputed the possible hypothesis that deficient levels of endorphins were somehow related to depression in patients. In 1979, Emrich et al found no differences in plasma beta-endorphin levels between depressed and nondepressed subjects. Pickar et al in 1983 also did a similar experiment and found no differences in cerebrospinal fluid samples (Willner 1985). They explained their results by hypothesizing that high endorphin levels were not specific to affective disorders such as depression, anxiety, anorexia nervosa and high stress disorders. Further measurements of opioid activity in the cerebrospinal fluid of depressed patients failed to demonstrate a deficiency of endorphins as related to depression (Almeida and Shippenberg 1991).
Using another method of examination, some researchers went about investigating the effects of mood using opiate antagonists such as naloxone and opiate agonists. It was concluded after some years of research that there was little evidence that opiate antagonists had marked effects on mood (Willner 1985). For instance, in 1977, Davis et al, 1979, Terenius et al, as well as Emrich et al found that low doses of naloxone administered to depressed patients showed no mood changes. Similarly the administration of high doses of naloxone in normal patients did not produce the expected depressive effects (Grevert and Goldstein 1978). Jones and Herning in 1979 and Pickar et al in 1982 showed that although a range of dysphoric feelings including depressed mood was found in normal subjects after injections of naloxone, effects mainly consisted of nondepressed feelings of irritability and anxiety (Willner 1985). Opiate agonists on the other hand should elevate depression symptoms, opposite to the hypothesized depressive effects of antagonists. After study, clinical use of full opiate agonists had revealed a wide variety of results. In some cases it has shown either no significant antidepressive effects, or mild antidepressive with major tranquilizing effects. The injection of beta-endorphin had shown effects varying from mild, to delayed improvement, to even switching into hypomaniac states (Rodgers and Copper 1988). Because of discrepancies such as these, it was premature at this time to attempt to draw any conclusions as to how, if at all, endogenous opiate systems might be involved in the actions of antidepressant agents and depression (Emrich 1982).
A recent experiment conducted by P. Tejedor-Real et al in 1995 has turned the field of endorphin-depression research in a different direction. He uses the learned helpless model of depression as the basis of his experiments. That is, rats in the experiment are taught helplessness via inescapable foot shocks in a small, dark, soundproof room that was brightly illuminated with a 100W light source. The rats' limited means of escape meant that helplessness was taught to the rats in order to induce a depressed state. This depressed state serves as the basis for antidepressant drug examination. After the preparations and training of the rats had been completed, the scientists observed the effects of several types of molecular compounds including Met-enkephalin, Leu-enkephalin, morphine, imipramine, naloxone, RB 38A or RB 38B during a helplessness test (Tejedor-Real 1995). (RB 38A is a mixed inhibitor of enkephalin degrading enzymes and RB 38B is a selective inhibitor of neutral endopeptidase E.C. 3.4.24.11 (NEP)).
In total, the rats were pretreated with 60 scrambled inescapable electric foot shocks. They were then subjected to escape and avoidance performances via shuttle-box. The animals were placed singly in the shuttle-box and subjected to 30 avoidance trials with 30 seconds breaks between trials. Escape responses required the rat to either avoid shock or escape an electrified floor grid by crossing a gate into the second compartment of the shuttle-box. These avoidance sessions were preformed for 3 consecutive days in the morning, and the number of escape failures and the intertrial interval (ITI) activity (the number of intersignal crossings) were recorded. After this conditioning, the animals were injected with the already decided treatments: met-enkephalin, leu-enkephalin, RB 38A, RB 38B, morphine, or saline control. In a further experiment, four groups of animals were treated with imipramine, naloxone, imipramine and naloxone, or saline control (agonists and antagonists respectively of the opiate system) (Tejedor-Real 1995).
Results showed that there is a possible neurochemical basis of endogenous opioid peptide relationships in the learned helplessness model of depression. The stimulation of the opioid system either by exogenous administration of met- or leu-enkephalin or morphine raised the levels of endogenous opioids which in turn reversed the escape deficit of rats after inescapable shock treatment. Though these results support the relation of elevated endorphin levels to reverse depressive effects of stress, naloxone treatments gave mixed results. In previous studies, naloxone had been found to potentiate the effects of uncontrollable stress. But naloxone, as found by others, should also be able to reverse the learned helplessness in specific experimental conditions. Naloxone prevented predicted learned helplessness in animals unable to escape when administered before exposure to the initial stress, but it did not revert this deficit when administered immediately before the shuttle-box test. These inconclusive results make it difficult to arrive at a conclusion that clearly clarifies the role of opioids in the learned helplessness model.
On the other hand, studies done with antidepressant drugs have come to support the endorphin link to depression. It has been found that tricyclic antidepressants interacts with the opioid system, accounting for the their antidepressant effects. In Tejedor-Real's study, naloxone reversed the positive effect of imipramine, a tricyclic antidepressant, which provides strong support for the opioid mediation of this and other antidepressant effects. Further evidence is provided in similar behavioral models of depression such as a forced swimming test that involves a stress and despair dimension where naloxone has also been found to antagonize the effects of tricyclic antidepressants (Tejedor-Real 1995).
Endorphin research has led to new, though conflicting findings in the field of mental illness. Throughout the years, evidence has existed that links an excess, deficiency, and even static levels of endorphin activity to depression. Further investigations may yield a new treatment for depression and should improve our understanding of the role of endorphins in normal and abnormal physiology (Li 1981). It has even been said that some patients in the future could be treated with their own endorphins, extracted under local anesthetic from their cerebrospinal fluid during a routine checkup visit and held in reserve for moments of mental crisis (Davis 1984). Perhaps research such as that done by Tejedor-Real will further provide evidence that will support the link between brain endorphin levels and depression and continue to build a case that will, in future years, give a basis for better, more effective biochemical treatment to a psychological disease.
References:
Almeida, O.F.X. and Shippenberg, T.S. Neurobiology of Opioids. Springer-Verlag Berlin Heidelberg. (1991).
Davis, Joel. Endorphins: New waves in Brain Chemistry. The Dial Press. (1984).
Emrich, H.M. A Possible Role of Opioid Substances in Depression in Typical and Atypical Antidepressants: Clinical Practice. (Costa, E and Racagni, G, editors). Raven Press (1982).
Li, Chao Hao. Hormonal Proteins and Peptides: Volume X: Endorphins. Academic Press. (1981).
Rodgers, R.J. and Cooper, S.J. Endorphins, Opiates, and Behavioural Processes. John Wiley & Sons. (1988).
Simon, E.J. & Hiller, J.M. Opioid peptides and Opioid receptors. Chapter 15 (pp 321-339) in Basic Neurochemistry: Molecular, Cellular and Medical Aspects (5th edition) (G.J. Siegal et al, editors). Raven Press (1994).
Tejedor-Real, P. et al. Implication of Endogenous Opioid System in the Learned Helplessness Model of Depression. Pharmacology Biochemistry and Behavior, Vol 51, No 1: 142-152. (1995).
Thompson, Hunter S. Fear and Loathing in Las Vegas. Random House (1972).
Wagner, John J. and Chavkin, Charles I. Neuropharmacology or Endogenous Opioid Peptides. Chapter 46 (pp519-529) in Psychopharmacology, 4th Edition: Generation of Progress. (Floyd E. Bloom and David J. Kupfer, editors). Raven Press (1995).
Willner, Paul. Depression: A Psychobiological Synthesis. John Wiley & Sons, 1985.
WWW 1. A Scientific Odyssey: People and Discoveries: Role of Endorphins Discovered 1975. http://cgi.pbs.org/wgbh/aso/databank/entries/dh75en.html. 1998 WHGB.
WWW 2. Endorphins: A Representative Family of Neuropeptide Neurotransmitter. http://www.williams.edu:803/imput/IB1.html. Williams College of Neuroscience, 1998.
WWW 3. Endorphins. http://members.home.net/pharmcentral/endorphins.htm. Theodore Nason, 1994-1999.
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