When an individual suffers severe pain due to an accident, illness, or surgery, doctors can alleviate it with painkillers. These substances help reduce the pain and the associated suffering, allowing the individual to regain functionality. However, opioid painkillers present a significant drawback: they can lead to addiction. Consequently, the decision to use them involves potentially serious consequences.
Addiction is a complex phenomenon driven by two main forces: positive reinforcement and negative reinforcement. Positive reinforcement occurs when drug use triggers a sense of euphoria, encouraging continual use as individuals seek to repeatedly experience this pleasurable sensation. Conversely, negative reinforcement comes into play when discontinuing drug use leads to unpleasant side effects that cause significant distress. To avoid these unwanted sensations, users are motivated to continue the behavior, often taking another dose of the painkiller to prevent the negative effects associated with its absence.
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The surge in fentanyl use in recent years has fueled widespread addiction
(Photo: Shutterstock)
Opioids of the masses
Fentanyl is one of the most powerful painkillers available today. It is a synthetic opioid, meaning it belongs to a class of man-made substances that resemble compounds derived from the opium plant or its products in both chemical structure and function. These substances bind to receptors in nerve cells in the brain, affecting their function. Fentanyl acts similarly to other opioids, such as heroin.The primary role of these receptors is to recognize naturally occurring opioids in the brain, helping us cope with anxiety, fear, and pain.
Fentanyl’s extreme potency makes it highly effective for relieving severe pain, but it also induces intense euphoria. The combination of its rapid onset, the intensity of the pleasurable sensations it induces, and the severity of withdrawal symptoms experienced upon cessation make the risk of addiction to it particularly high.
Prolonged use of fentanyl can lead to dependence, with individuals becoming addicted to fentanyl and experiencing significant withdrawal symptoms when trying to quit. Addiction often results in dose increase, sometimes leading to death from overdose. Data from 2003 to 2017 indicate that excessive use of fentanyl has transformed in recent years into a full-scale epidemic.
Separate Mechanisms
Despite the widespread use of fentanyl, the precise processes occurring in the brain during its use—and what happens when users attempt to quit—remain unclear. To better understand these mechanisms, researchers from Switzerland and France recently employed advanced scientific tools to study brain activity patterns associated with fentanyl addiction.
In a study published in Nature, mice were injected with fentanyl for five days, followed by naloxone, a substance that neutralizes opioid effects and is commonly used to treat overdoses. This administration triggered withdrawal symptoms in the fentanyl-addicted mice. The researchers observed increased activity in the ventral tegmental area (VTA) of the mice’s brains—an expected outcome, as this area is integral to the brain’s reward system and the generation of feelings of euphoria.
The researchers found that fentanyl suppresses the activity of neurons responsible for reducing neural activity associated with the sense of reward in the VTA. As a result, the reward mechanism becomes more active. Once fentanyl administration stopped, the mice displayed signs of withdrawal, and the amygdala, a brain region involved in fear learning and negative emotions - became active, seemingly reflecting the severe discomfort associated with withdrawal.
Using genetic engineering, the researchers deleted fentanyl receptors from neurons in several brain regions. When the receptors were removed from the VTA, the positive reinforcement caused by fentanyl was diminished. However, to the researchers’ surprise, the addiction symptoms and withdrawal difficulties remained unchanged, suggesting that the mice did not derive much enjoyment from the drug, but still became addicted and experienced withdrawal.
In contrast, when the fentanyl receptors in the amygdala were deleted, the mice did not exhibit withdrawal difficulties. This indicates that the mechanisms of positive and negative reinforcement rely on distinct brain mechanisms, representing two distinct systems in the brain.
Reinforcements in separation
To confirm their findings, the researchers conducted additional experiments. First, they gave the mice a lever that, when pressed, suppressed the activity of neurons responsible for inhibiting the VTA neurons. The mice quickly learned to press the lever and enjoy the pleasant sensation it provided. Next, the researchers injected the mice with fentanyl.Since fentanyl independently suppresses the activity of the same inhibitory neurons, the mice experienced satisfaction from the drug’s pleasant effects and pressed the lever less frequently. This suggests that fentanyl indeed acts by inhibiting the neurons that restrain the VTA, providing positive reinforcement for drug consumption.
To confirm the negative reinforcement mechanism associated with fentanyl, the researchers activated neurons in the amygdala that respond to fentanyl and trigger negative sensations over an extended period. Then, they provided the mice with a lever that halted the activity of these neurons. The mice pressed the lever repeatedly seeking relief from the distress caused by the addiction-associated brain activity
At the next stage, the researchers injected the mice with fentanyl, just as in the previous experiment. The fentanyl suppressed the activity of the amygdala neurons, improving the mice’s well-being and reducing their need to press the lever. This demonstrates that fentanyl indeed mitigates the negative sensations associated by amygdala activity, creating a form of negative reinforcement that encourages continued drug use.
The study's findings change our understanding of the positive and negative reinforcements that drive addiction. Rather than being two sides of the same phenomenon, these reinforcements appear to involve distinct mechanisms, each linked to separate groups of neurons, with the activation of one system not necessarily triggering the other. Given the rising trend in opioid painkiller use, research in this direction could influence how these drugs are prescribed and guide the development of new treatments to assist with withdrawal.
The current study was conducted on mice, and further research using non-invasive methods is needed to determine whether humans exhibit a similar separation between the mechanisms responsible for positive and negative reinforcement. Nonetheless, these findings already offer a glimmer of hope for the many individuals struggling with painkiller addiction. The better we understand how the brain functions during the addiction process, the better our chances of helping people overcome their dependency.
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