What has NARCAN got to do with morphine overdose?

I was seeing a movie one time titled Count down(A bit scary also), the movie was about an app, and anyone who downloaded it would know when they would die, After a series of events, a particular nurse who just got her license downloaded it just for fun till it became serious. Then I got to a scene where her time was almost up but to alter the prediction of the app she overdosed herself with morphine and her heart stopped beating(before the time predicted she would die) then the demon behind the app vanished. In the course of her sister wailing, she noticed that NARCAN was inscribed on her sister's body(the nurse), she checked her pocket and saw a bottle of NARCAN with a syringe, injected her dead sister with it and she gasped back to life. Intriguing story right??? I agree... But the last event got me thinking🤔

What has NARCAN got to do with morphine overdose?

Before heading there let’s take a simple tour around these terms.

Morphine is an efficacious opioid drug or medication used majorly in the medical field for the relief of mild or severe pain, in simple terms morphine is an effective pain reliever.

Morphine Structure

Morphine Injection dose

Morphine is a naturally occurring narcotic analgesic/anaesthetic in the sense that asides relieving pain, it also induces sleep. It is gotten and isolated from the milky latex (of resinous texture) found in the unripe seed capsule of the poppy plant or opium poppy, Papaver somniferum from the flowering plant Papaveraceae where morphine alongside other opioids are derived from.
The poppy plant is a plant that have high alkaloid producing content thereby making morphine one of its many alkaloids, codeine, narcotics, thebaine, etc. also being few out of many.

Opium poppy

How does morphine do it?

Morphine acts directly on opioid receptors present in the Central Nervous System(CNS) and lessens the feeling of pain by getting in the way of nerves signalling pain to the brain and the body.
Opioid receptors are group of inhibitory G protein-coupled receptors with the opioids acting as ligands. This G protein coupled receptor(GPCR) otherwise known as “Guanine nucleotide-binding” protein coupled receptor, is situated in the cell membrane that binds extracellular substances(in this case morphine which is our case study) and relay signals from these substances to an intracellular molecule known as G-protein(guanine nucleotide binding protein).

GPCR is composed of a long protein that has three major regions; an extracellular portion known as the N-terminus, A middle portion containing seven transmembrane domains and intracellular portion known as the C-terminus.
When a GPCR attaches to a ligand e.g morphine(a molecule that has an affinity towards the receptor), the ligand stirs up in the transmembrane region of the receptor; a change in the conformity( i.e its usual configuration). This affinity triggers the C-terminus which releases a substance that activates the G protein linked to the GPCR.

Activation of the G-protein ignites a series of intracellular reactions that terminates eventually in the generation of some obvious responses or effects.
Morphine which is an opioid serves in this case as the ligand and the opioid receptor, the GPCR. After attaching itself to the opioid receptors located on the nerve cells, spinal cord, digestive tract and other parts of the body, the responses triggered by this affinity includes blocking pain messages sent from the body through the spinal cord to the brain and this is done efficiently by inhibiting the ability of sensory nerves to respond to stimulus especially one causing.

These opioid receptors are grouped into; mu-receptor(MOR), kappa-receptor(KOR), delta-receptor(DOR), nociception receptor(NOR) and zeta receptor(ZOR). These receptors were named based on the first letter of the first ligand that was discovered to bind to them. Morphine was first found to bind the “mu” receptors, M for morphine in correspondence to the Greek lowercase letter(μ). These receptors are further subdivided into: mu1, mu2, mu3, kappa2, kappa3, delta1 and delta2.

mu1,2,3 receptors(MOR) bind to endogenous ligands like endorphin(which performs similar function with it’s exogenous ligand counterpart-Morphine that induces pain relief).

The mu-1 receptor is responsible for analgesia and dependence
The mu-2 receptor is vital for euphoria, dependence, respiratory depression, miosis, decreased digestive tract motility/constipation.
The mu-3 receptor causes vasodilation.
Kappa receptors(KOR) binds to dynorphin A and B (prodynorphin as the precursor). They produce analgesia, diuretics and dysphoria.
Delta receptor(DOR) bind to encephalitis(precursor being proenkephalin). They play a role in analgesia and reduction in gastric motility.
Nociceptin receptor(NOR) binds to nociceptin/orphanin FQ (pre-pronociceptin is the precursor) causing analgesia and hyper analgesia(depending on the concentration).
Zeta receptors(ZOR) regulates developmental events in variety of normal and tumorigenic tissues and cells.

Morphine alongside other opiate alkaloids aside mu-receptors, are known to bind to delta and kappa opioid receptor subgroups.
Morphine is known for triggering analgesic effects after binding with the above stated receptors. It is also known to be a natural vasodilation used by medical practitioners in the treatment of hypertension(reason being that morphine affects the parasympathetic nervous system by widening the blood vessels that supply oxygenated blood to areas that need them and in doing so drops the blood pressure within the walls of the blood vessels). Due to the lowering of the blood pressure, the body automatically becomes weaker and tired, thereby inducing sleep.

What’s NARCAN's place in all these?

NARCAN also called Naloxone(C₁₉H₂₁NO₄) is a life-saving medication known for its ability to bind to opioid receptors and reverse the effects of overdose of opioids like Morphine.

Naloxone structure

Naloxone is synthetically derived from oxymorphone; a highly potent opioid analgesic known as a remedy for intense pain derived from thebaine which is also a constituent of the poppy plant. The drugs differ in that the methyl group on the nitrogen atom in oxymorphone is replaced by an allyl group in naloxone.

Oxymorphone structure

Thebaine Structure

Due to the analgesic effect of morphine, a large tendency for abuse and addiction is possible, morphine binding to the opioid receptor(mu to be specific), ignites dependence by the receptors leading to addiction and therefore overdose. When morphine is taken to relieve pain, it temporarily blocks and hinders pain signals from reaching the brain. The pain sensory nerves can be likened to a threshold, if pain relievers are taken, it temporary blocks the pain signals but weakens the threshold in that the body becomes accustomed to a particular kind of pain and the medications used do not work any longer cause the threshold have been levelled down and so in order to get the pain relieving effect, the medication is increased especially in instances of intense pain and this can lead to overdose due to tolerance or dependence and in extreme cases; addiction.
When this overdose occurs, there is an excessive analgesic effect in that the blood pressure becomes extremely low and slows down breathing, NARCAN in this case serves as an antidote or an antagonist to opioids, designed to reverse the harmful effects of opioids overdose.

Due to the rising numbers of deaths caused by opioids overdose, NARCAN was designed to offer a life-saving treatment till the medical team intervenes(more like a first-aid for opioid overdose), it is part of the emergency overdose response kits administered to people likely to experience opioid overdose or those likely to encounter people that have tendency of opioid overdose(e.g family, friends, neighbours and medical practitioners, etc.)

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Statistics of individuals that die from opioid overdose from Year 1999- 2020

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Naloxone Injection

NARCAN or Naloxone after being administered is only effective for approximately an hour compared to some opioids that leaves a long lasting effect of 9-12 hours so patients after NARCAN administration must be monitored closely, In most cases, it is advisable to call for medical back up even after administering NARCAN to prevent the occurrence of patients indulging in a second overdose which may become more severe than the first.

The drug is highly lipophilic, allowing it to rapidly penetrate the brain and to achieve a far greater brain to serum ratio than that of morphine.

Naloxone can be administered by

Injecting Intravenously(through the veins)
Injecting intramuscularly
Nasal spray.

In most cases multiple doses of naloxone is required when the opioids overdosed have a longer action time and stronger effect than naloxone itself.
Naloxone reverses all the negative effects caused by opioids like morphine by;

Increasing the heart rate
Increasing blood pressure
Reversing respiratory depression and so on.

So next time you see a case of opioid overdose, don’t panic. NARCAN can save the day🤭.

References