Opioid antagonists

Opioid antagonists, like the name suggests, are medications that block opioid receptors. They’re used mainly to urgently reverse the side effects of opioid agonists and to help individuals who are recovering from opioid use disorder.

Now, opioids work by binding to opioid receptors in the brain, spinal cord, and gastrointestinal tract. Some are endogenous, meaning they are produced naturally by the body, like endorphins, named for “endogenous morphine” due to their similar effects in the body. But others are exogenous, meaning they come from outside the body, like heroin and morphine, which come from the opium poppy; a flowering plant that oozes a milky white liquid.

To understand how opioids work, let’s zoom in on a region of the spinal cord that has opioid receptors. Normally, in the absence of endorphins, nociceptive fibers carry pain signals from the body to the dorsal, or posterior, horn of the spinal cord, where they release neurotransmitters like glutamate, substance P and calcitonin gene-related peptide. These neurotransmitters cause pain signals to be transmitted to the brain via ascending pain pathways.

Now, let’s say someone goes to play a rigorous game of badminton. Exercise releases endorphins which activate the three major opioid receptors located on neurons, called the mu, kappa, and delta receptors. As endorphins or other opioids bind to these receptors on the presynaptic terminals of nociceptive fibers, they inhibit the opening of calcium channels, preventing calcium influx, and thereby blocking the release of pain-causing neurotransmitters like glutamate, substance P and calcitonin gene-related peptide. At the same time, endorphins also bind to postsynaptic neurons, opening potassium channels here, leading to hyperpolarization and decreased excitability of the neuron. These effects together reduce the transmission of pain signals to the brain.

Now, opioids also have action on the body’s dopaminergic, noradrenergic, and serotonergic pathways.

In the brain’s reward pathway, located in the midbrain, opioids bind to receptors on inhibitory GABAergic neurons, causing a decrease in the release of gamma-aminobutyric acid, also known as GABA. This, in turn, leads to less inhibition of dopaminergic neurons and therefore more dopamine. This increase in dopamine is why opioids cause feelings of pleasure or euphoria.

For the noradrenergic effects, opioids inhibit noradrenergic neurons in the brain, especially in the locus coeruleus, leading to a decrease in norepinephrine release. This contributes to the sedative effects of opioids.

Last, certain opioids activate neurons that release serotonin in the spinal cord, helping to reduce pain transmission.

Now that we’ve covered how opioids work, let's talk more about some of the unwanted effects. There are opioid receptors throughout our body, like in the gastrointestinal tract. So, when a person receives a dose of morphine, it could also result in a series of unwanted side effects, like nausea, vomiting, and constipation.

Other side effects of opioids include pupillary constriction as well as flushing.

However, the most dangerous side effect is respiratory depression, caused by decreased activity in the medulla; the part of the brain that regulates breathing. This happens when a person overdoses on an opioid, like morphine, fentanyl, or heroin.

Respiratory depression can be life-threatening and should be treated right away - because the person can literally stop breathing.

Also, watch out for central nervous system depression, which can lead to coma, and cardiac problems like bradycardia and other arrhythmias.

Now in order to treat opioid overdoses, we can use an opioid antagonist like naloxone. Naltrexone on the other hand, is a medication that is helpful as maintenance therapy in opioid use disorder and alcohol use disorder. Other opioid antagonists like methylnaltrexone and alvimopan can help counteract opioid-induced constipation. These medications all bind strongly to opioid receptors without activating them.

Since naloxone has a higher affinity for opioid receptors than opioid agonists like morphine, fentanyl and heroin do, it actually displaces the agonist from the receptor and doesn’t allow another to bind. Naloxone readily crosses the blood-brain barrier and has a rapid onset and short duration of action of 1 to 2 hours.

So, when it’s given intravenously or intranasally, it can reverse the central effects of opioids within minutes, potentially saving a person’s life.

Another potential use of naloxone, is to detect when a person is physically dependent on opioids. Although not commonly done, this can sometimes be useful before starting a long-acting medication like naltrexone to help manage opioid use disorder.