Index of Page
GENERAL BACKGROUND
From opium to opioids. . .what’s the connection?
Why do we have the endogenous opioid system?
OPIATES
What is the molecular structure of Opiates
The effects of opiates on behavior
How does the structure affect function?
The Blood Brain Barrier and opiates
OPIOIDS
How do they exert their effects?
Current research
with autism has yet to delineate a clear cause for any of the assortment of symptoms
associated with disorder. However,
many promising theories have emerged. These theories have been
difficult to prove definitively in a clinical setting, but the underlying logic and
the strong correlations are encouraging. The
theory we have chosen to investigate is the Opioid Excess Theory, due
to its intriguing insight into this disorder. This area of the web page is designed to provide a basic
background on opioids in order to supplement the material presented on its
relationship to autism in the next section.
Morphine, opium, and heroin are perhaps the most well known opiates, with the history of their recreational and medicinal use extending well into our past. Of these, opium is the oldest. The first known record of its use dates back to the writings of Theophrastus in 300 B.C. Opium is derived from the juices found in the seeds of the opium poppy, Papaver somniferum, and its active ingredients make up nearly twenty-five percent of its powdered weight. Originally, opium was administered as a vapor, or through punctures in the skin. However, the combination of variables involved in absorption as well as the purity of the opium lead to problems with overdoses during a time when the only methods for resuscitation involved smelling vinegar or other acrid substances. Later, in 1803, a German chemist isolated the active ingredient of opium. These effects were much more predictable than typical opium administration, which was more of a “cocktail” of drugs, where the ratios varied between plants. He called this active ingredient morphine, after Morpheus, the god of dreams. Administration was further enhanced in 1853 following the advent of the syringe by Pravaz and the hollow needle by Alexander Wood.
Once the effects of opium were observed, many wondered how it was able to exert these effects, and began to explore the possibility of an endogenous molecule that paralleled opium. In doing so, they discovered the endogenous opioid system, named after its exogenous cousin opium. At this point it is important to differentiate between the endogenous and exogenous compounds that act on the same class of receptors. The term ‘opioids’ refers to compounds found within a living system, or endogenous compounds, while ‘opiates’ refers to compounds supplied by an external, or exogenous source (i.e. drugs).
The effects of the opioid system gave rise to questions concerning the purpose of having receptors that elicit these properties. More importantly, why would this system have evolved? One reason seems fairly obvious: a natural analgesic. Analgesia is a term used to describe something that inhibits the perception of pain. Thus, being able to supply your own painkillers would prove advantageous in a time when salicylic acid (aspirin) and acetaminophen (Tylenol) were unavailable. And more importantly, endogenous painkillers do not require that an individual has the time to take an exogenous supply and then wait for it to be processed by the body and presented to the appropriate receptors (i.e. take two aspirin and call me in the morning). An endogenous pain suppressor means that when an animal is in a life or death situation, and it is injured, it will be much less sensitive to pain and therefore it will not be hindered in terms of mobility if it needs to escape the dangerous situation.
The activation of reinforcement circuits is equally important from an evolutionary standpoint. The release of endogenous opioids occurs when an animal is threatened, such as an instance where it is fighting, or when the animal is mating. Both of these situations directly effect the survival of the animal, as well as its genes. The endogenous opioid system inhibits the effects of pain, while also stimulating positive reinforcement which will encourage the animal to keep doing what it is doing. This could explain why, in the heat of a fight, a normally cool and collected person may continue fighting. After examining the opioid system on a behavioral scale, it is important to include a discussion of the molecular actions of these drugs in order to provide further insight into their nature.
As mentioned above, opium is a “cocktail” of drugs. It is approximately 10% morphine, 6 % narcotine, 1% papaverine, and 0.5 % codeine, as well as many other minute quantities of different drugs. Of these, morphine and codeine are the most well known, and have the greatest use in the medical field. Codeine is a less potent analgesic (pain killer) but it also has fewer psychological side effects. The molecular structure was not identified until 1925, with the work of Gulland and Robinson. Once its structure was identified, chemists and pharmacologists began working to synthesize similar compounds, while also analyzing modifications to morphine that had been made in the past. For example, one such modification lead to the development of heroin in 1874. At the time, this new drug was thought to be more potent than morphine, while also lacking the addictive properties of morphine. Since then, however, the molecular structure of heroin has been identified, allowing researchers to understand how it is metabolized in the body. The only structural differences between the two molecules lie in the replacement of two –OH groups (hydroxyl) on morphine with two –OCOCHs groups (acetyl) in heroin. This change makes heroin much less hydrophilic, a great advantage in the world of pharmacology.
Adapted from Neuropsychopharmacology
Before exploring the subtleties of the endogenous opioid
system, it might help to go over the observed properties of opiates (exogenous)
because their effects are much more pronounced, as well as familiar.
These drugs elicit a feeling of euphoria in humans, as well as decreased
sensitivity to pain, sedation and reinforcement.
Because they are able to stimulate the reinforcing circuits of the brain,
these drugs are highly addictive, resulting in their careful and restricted use
in the field of medicine. People
who become addicted to them experience both a dependence on the drug, as well as
a tolerance for it over time. Dependence
refers to the negative visceral consequences associated with withdrawal, while
tolerance refers to the progressive adaptation to dosages, eventually requiring
higher dosages to elicit the same effects.
So just what does hydrophilic mean? Literally, hydrophilic means “water loving” so it refers to any compound that is attracted to water, or readily dissolves in an aqueous (water) solution. In contrast, a hydrophobic compound is a “water hating” compound, and does not dissolve easily in an aqueous solution. Such compounds are typically highly soluble (easily dissolved) in lipids (fats). To make an analogy, think of oil and vinegar, where vinegar would be the hydrophilic compound, and oil the hydrophobic compound. So why is morphine hydrophilic while heroin is hydrophobic? The answer lies in the different “groups” attached to the molecules. Hydroxyl groups contain an oxygen atom bound to a hydrogen atom. Such an arrangement causes the electrons to be localized around oxygen, giving it slight charge. This charge will interact easily and readily with water, but not lipids. The acetyl groups on heroin, on the other hand, do not have a charge associated with them, and instead interact well with lipids. This means that heroin will cross the blood brain barrier (BBB) more readily.
The blood brain barrier protects the brain from harmful toxins found in the blood. It prevents these compounds from harming the delicate (and irreplaceable) cells of the central nervous system. How does it work? Blood flows to the brain in arteries, which reach the central nervous system and then branch into thousands of capillaries, which provide blood (containing much needed oxygen and nutrients) to the brain. These capillaries are made out of endothelial cells, which are very much like skin cells in that they are very flat. These cells comprise the “wall” of the capillaries, and when they are near the central nervous system, they are very well glued together (like the mortar between bricks), unlike in other areas of the body where large gaps exist. This means that unless a compound is highly soluble in lipids, it will be unable to enter the brain unless it is actively transported in. As a result, morphine does not cross the BBB readily, while heroin does.
This difference means that even though heroin is metabolized into morphine within the body, it will exert its effects much faster because more if it is able to cross the BBB. It is important to note that morphine does not exert its effects solely in the brain, it acts throughout the body, but the psychological effects of morphine stand out the most and these effects are produced from morphine’s activity within the brain. As a result, while heroin was originally thought to be a non-addictive form or morphine, it is simply a more potent, equally addictive form.
The endogenous opioid system was first verified in 1975, by
the work of two separate laboratories (Hughes, 1975 and
Terenius and Wahlstrom,
1975). The first of these
identified peptides were named “endorphins” from “endo-” meaning “from
within” and “-orphin” being the root of many of the opiates. Those substances found in the head were called
“enkephalins” for the Greek meaning “from the head.”
All of these compounds are peptides, which means they are very short
proteins.
In all, there are three types of endogenous opioids that exert their effects on the central nervous system. For this reason, they are known as neuropeptides, or neuromodulators. Neuropeptides, or neuromodulators are somewhat different from the “traditional” neuroactive peptide (i.e. neurotransmitters). For example, neuropeptides are only synthesized in the soma while neurotransmitters can be produced on demand at the axon terminal. (See picture below for better understanding) Also, while neurotransmitters are packaged into re-usable membrane vesicles with a high concentration, neuropeptides are carried in larger, densely staining vesicles that are not re-usable. Further, neurotrasnmitters are released at a special area of the terminal bouton known as the active zone while neuromodulators are not. The three major classes of opioid peptide are known as enkephelins, b-endorphin and dynorphin. All three have a shared tetrapeptide sequence in their amino acid sequence: tyrosine-glycine-glycine-phenylalanine. The amino acid sequence is the basic molecular chain of a protein.
Typical neuron. Adapted from Carlson's Physiology of Behavior.
Each of these molecules has a different precursor and is synthesized in different areas of the brain. Proopiomelanocortin (POMC) is the precursor for b-endorphin, and is synthesized in discrete areas of the brain such as the basal ganglia, cortex, and amygdala, the hypothalamus and the pituitary. The basal ganglia is located deep within the brain and is very important in motor activities. The cortex is found on the very outside of the brain, and receives sensory inputs, sends out motor outputs, and also processes information. The amygdala is part of the limbic system and is therefore very important in memory, as well as emotions. The hypothalamus and pituitary are important for the overall regulation of the body through hormones and other molecules. Prodynorphin (PDYN) is the precursor for dynorphin, and is also found in many areas of the brain, as well as the spinal cord.
For those who are not familiar with second messenger systems, a G-protein linked receptor is a type of receptor whose long protein chain is sort of “stitched” into the membrane of a cell so that is crosses the membrane seven times. This means that one end of this “protein thread” will face the external environment, while the other will face the internal environment. When the appropriate molecule binds to the external end, it causes the internal end (or “cytoplasmic tail”) to change its structure slightly. This change in structure causes the internal end to detach from the G-protein it normally attaches to, thus allowing the G-protein to become active. Once active, the G-protein breaks into two parts which can then activate other proteins, eventually leading to an internal change for the cell, such as turning on or off a gene. This is an important type of second messenger system.
Unactivated. . .
Activated. . .
Schematic of a G-protein linked receptor. Adapted from Essential Cell Biology
The µ receptors seem to be localized to the periaqueductal gray matter, the ventral medulla and the superficial horn of the dorsal spinal cord, all of which are important areas in the regulation of pain. In fact, drugs such as naloxone, which neutralize these receptors, thus preventing the binding of opioids or opiates, have been shown to counteract the effects of morphine. Naloxone has also been used in the treatment of autism, with some success. Morphine is highly selective for the µ receptor. The enkephelins have been shown to act at the µ and d receptors while dynorphin has been shown to act at the k receptor. These receptors are also located in areas that are important for the perception of pain (nociception).
Current evidence suggests that the µ receptor is responsible for the pronounced analgesia as well as the reinforcing mechanisms. Agonsits (things that increase the likelihood of a neural event) to the µ opioid receptors are addictive because activation of this receptor produces an inhibitory effect on the GABA-ergic neurons that normally suppress the dopaminergic neurons in the ventral tegmental area. GABA is another type of neuromodulator found in the central nervous system, and has been shown to have strong inhibitory effects. These inhibitory effects are due to the fact that GABA makes it harder for a neuron to send an electrical message. The details of this are not necessary to understand in this context. So, because activating the µ receptor inhibits the inhibitors (the GABA-ergic fibers), those cells that used to be inhibited by the inhibitors are now active. It may take a moment for that to soak in. In this case, the neurons that are normally suppressed by GABA are dopamine neurons. This causes an increase in the release of dopamine, which is strongly correlated with reinforcement and addiction, hence the reason that drugs like morphine are so addictive. The ventral tegmental area (mentioned above) is part of the mesolimbic system (one of the four dopaminergic systems). Therefore, in summary, by inhibiting the neurons that normally suppress the release of dopamine, drugs such as morphine cause an increased release of dopamine, and therefore reinforcement.
In terms of the affects of opioids and opiates on pain, the most important area is the spinal cord. In the area of the spinal cord where incoming pain information is localized, (superficial dorsal horn) there are many interneurons that contain dynorphin and enkephalins. Interneurons are very small neurons located between the larger neurons that project between longer distances. These interneurons modulate the information sent and received by these larger neurons. All three receptors types have been found in this area. These interneurons inhibit the postsynaptic nerve, making it harder for it to fire its “ow!!!” message, while also inhibiting the presynaptic neuron’s release of neurotransmitters that provide the initial signal for that “ow!!” It might help to view the picture of a neuron above, for a better understanding.
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