Biochemistry of Morphine: How It Can Help and Hurt

In our previous blog post, we discussed the structure of morphine and other opioid analgesics.  These substances all have similar chemical structures, and these structural similarities lead to the similar effects that these opioids have.  In this post, we’ll be specifically discussing the effects of morphine on the body.  From our previous entries, it is known that morphine’s chemical formula is C17H19NO3.  These elements are organized in a way often called the morphine rule, and other opioids also obey this rule. Additionally, the structures of morphine and the opioids that are derived from it are similar to endorphins and enkephalins, which are substances that the brain naturally produces. These natural substances also have analgesic effects, and since opioids are similar in structure to them, opioids also can stimulate pain receptors in the way that endorphins and enkephalins can. However, since opioids do not have exactly the same structure as endorphins and enkephalins, they are able to cause side effects. Let’s examine some of these effects.

 Biochemistry of Morphine’s Positive Effects

Pain is caused by intense or damaging stimuli. To avoid this unpleasant feeling of pain, people use morphine. Morphine is capable of blocking the pain receptor sites on the nerve cells. It is considered one of the most powerful pain relievers available, but what is the reason behind it being so effective? In this case, since the topic is about the interaction between a chemical and some receptor, there is a lock-and-key mechanism at effect. A molecule which can bind to a receptor is called a ligand, so in this case morphine is a ligand. The circumstances of the ligand being able to bind to the receptor are specific to the size, shape, and charge composition of both. There lies the idea behind the key, the molecule, and the lock, the receptor. If a ligand has the correct structure and charge to fit into a specific site on the receptor, known as the active site, it will bind to the receptor and effect some characteristic of the receptor cell, but we won’t go too deep into that. We’re here to talk about the chemistry of morphine, so let’s take a look at how morphine is the key to blocking pain receptors.

The structure of morphine is reproduced to the right. It is known as acentrally acting analgesic, a category of analgesics that includes opioids and acts on primarily on the brain and spinal cord, making it so capable of being a painkiller. As is apparent from its structure, it contains a benzene ring and various other chemical groups, such as a hydroxyl group and other carbon rings. The morphine needs a specific receptor to bind to in order to be effective. Morphine is known to bind to a specific subset of receptors known as opioid receptors. There are different types of opioid receptors such as kappa (κ)-,mu (μ)-, and delta (δ)- receptors, which differ by functional properties, side effect profiles, genes and proteins, and tissue expression patterns. These receptors are found on nociceptors, the sensory neuron cells that are responsible for sending pain signals to the brain as a response to damaging stimuli. Now that both the key and lock have been defined, the process of binding can take effect. The important characteristic to note in the structure of morphine is that the benzene ring is contained in one plane, so it is completely flat. It is perfect because it is then able to fit snugly against a flat section of the receptor’s active site. The rest of molecule falls into place easily. The neighboring carbon atoms fit into a nearby groove, while the nitrogen atom is able to attach to a negatively-charged group on the receptor, thus binding the ligand to the receptor.

The ligand has been bound to the nociceptor, so the morphine is able to work about dulling the pain. It accomplishes that by simply blocking the pain signals from being sent by the pre-synaptic neuron on the nociceptor. This is done by activating the opioid receptors, causing a reactionary change in the cell, which inhibits the production of substance P, a compound that is responsible for the synaptic transmission of pain and nerve impulses. Refer to the diagram to see a visualization of this process. However, it is a dangerous effect since the slowing of the nerve cell’s function and impulse release could lead to slowing in vital processes such as respiration, resulting in respiratory depression, a negative side effect amongst many.

This diagram is a visual interpretation of the process of blocking the release of substance P by activating opioid receptors, which morphine and endorphins can both do.

 Neurological Side-Effects and Addiction

In addition to stimulating the receptors that process pain signals, morphine is capable of stimulating other regions of the brain, especially the ventral tegmental area of the brain, which processes the release of reward compounds that are released when the human does something that aids survival. Doses of morphine are able to inhibit a process called long-term potentiation, in which the connections between neurons, or synapses, are made stronger through repeated simulation. As a result of long-term potentiation, the brain’s memory capacity is reinforced and made stronger as a result, since strengthened synapses are the basis for memory. Specifically, morphine effects the synapses between inhibitor neurons and dopamine neurons in the ventral tegmental area of the brain.

Pictured here is a dopamine neuron releasing dopamine, depicted as yellow-green circles, to a nearby neuron. Dopamine is responsible for making humans feel “good.”

Dopamine is a reward compound in the brain, being released whenever a human does something that makes them feel good, and inhibitor neurons serve to control the release of dopamine. The morphine removes the link between the inhibitor neuron and the dopamine neurons, so the dopamine neurons produce dopamine uninhibited with the connection to the inhibitor being removed. Thus, the human feels more rewarded since more dopamine is being processed by their receptors, but it takes more dopamine for the human to feel satisfied since the increased dopamine levels of the brain are imprinted into the memory since the morphine stimulates the synapse. Morphine chemically changes the brain by doing this, and it can cause dependence and addiction because of this.

Other Negative Side-Effects

Although morphine and other opioid analgesics primarily work with the brain, some of the side-effects of ingesting these substances affect different areas of the body.  These effects have a variety of causes, and many of these are independent from the structure of the opioid, contrary to the neurological effects.  Similar substances such as morphine, methadone, oxycodone, and hydrocodone can cause serious consequences as side-effects.  Some may even say that these unfortunate effects may render these drugs “not worth it.”  Many of the positive effects of these helpful drugs are only temporary.  For example, when morphine is used as a pain-killer, it is often used for only a short period of time.  The pain is temporary, and once it is relieved, the medication is no longer needed.  However, many of these side-effects are chronic.  As mentioned earlier, addiction can be caused by prolonged usage of opioids.  One’s body becomes trained to require treatment and medication in a process of addiction.  When these substances cease to be taken, the body undergoes withdrawal and many related side-effects.

Pictured here is a woman who is suffering from opioid-induced hyperalgesia after long-term opioid use.

After long-term opioid use, the body can become extra-sensitive to painful stimulation.  This condition is known as opioid-induced hyperalgesia, and although it is induced by nociceptive sensitization in the brain, it affects the entire body.  This state is caused by the inhibition of pain signals, and the alteration of the responsible receptors due to exposure to opioids.  Another long-term side-effect is particularly rampant in males.  This is the lowered production of sex hormones, notably testosterone.  Opioid-induced hypogonadism, as it is called, relates to the inhibition of the endocrine system after long exposure to opioid analgesics.  Consequently, when the body is subject to an imbalance of hormones, a domino-like effect can be caused, and in the case of opioids, people can develop osteoporosis.

These effects, both good and bad, show just some of the things that opioids can do to the human body.  Although these drugs are often used to ward off pain in medical circumstances, if used incorrectly, much like any medication, they can be devastating.  Avoid overdosing or becoming addicted to these substances, and only use them when told by a doctor.  Come back next time to read about methamphetamine, the most abused hard drug in the world, as declared by the U.N. World Drug Report in 2006, and how Heisenberg created it on the hit show Breaking Bad.

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