Opioids (such as oxycodone, morphine, heroin, fentanyl) bind to μ-opioid receptors (MOR) on specific nerve cells. In the brain’s reward circuit—especially in the ventral tegmental area (VTA) and the nucleus accumbens (NAc)—MOR activation switches off local GABA neurons that normally act as a “brake.” Without the brake, dopamine neurons fire more, flooding the NAc with dopamine.

This strong signal reinforces learning to seek the drug again. Over time, the system adapts (tolerance), and when the drug is stopped, withdrawal syndrome appears—key signs of dependence (NIDA).

Step by step: from opioid dose to dopamine increase

1. Binding: Opioids activate MOR (Gi/o protein-coupled receptors) throughout the reward circuit. MOR activation inhibits neurons by reducing calcium entry and increasing potassium exit (Trieu et al., 2019).
2. Disinhibition in the VTA: Many MOR are found in GABA interneurons that normally limit the activity of VTA dopamine neurons. Opioids hyperpolarize these GABA neurons, releasing the “brake” and disinhibiting dopamine neurons (Fields & Margolis, 2015).
3. Dopamine release: Disinhibited dopamine neurons in the VTA increase their phasic firing, elevating dopamine in the NAc—a key signal of reward and reinforcement (Nestler, 2014).
4. Association learning: Dopamine spikes strengthen associations between stimuli and drug (classical conditioning), focusing attention and behavior on seeking the substance (Volkow & Morales, 2015).

How repeated use can lead to dependence

• Tolerance (neuroadaptation): With chronic use, cells counter MOR signaling (e.g., by increasing cAMP/PKA pathways) and altering synapses in the VTA and other regions. Larger doses are required for the same effect (Nestler, 2001).
• Withdrawal: In stress and arousal centers like the locus coeruleus (LC), chronic opioids increase cAMP signaling. When the drug is stopped, LC neurons become hyperactive, producing physical withdrawal symptoms (anxiety, sweating, rapid heartbeat) (Koob & Volkow, 2016).
• Compulsive use: Addiction involves not only reward but also habit, motivation, and executive control circuits, making drug-seeking persist despite harm (NIDA—Understanding Drug Use).

Main brain areas (simplified map)

• VTA: “Origin” of reward dopamine; opioids here remove the brake on dopamine neurons (Trieu et al., 2019).
• NAc (ventral striatum): Receives dopamine; encodes reward and reinforcement (Nestler, 2014).
• Prefrontal cortex: Normally helps with self-control; its regulation weakens with chronic drug use (Volkow & Morales, 2015).
• Locus coeruleus: Noradrenaline center related to tolerance and withdrawal (Koob & Volkow, 2016).

Why this matters for treatment

Treatments that reduce MOR activation (e.g., buprenorphine, methadone) stabilize these circuits and blunt the dopamine spikes produced by illicit opioids, helping patients regain control as the brain recalibrates (NIDA—Medications for Opioid Use Disorder).

1. Ancient origins

The use of opioids dates back more than 5,000 years, when Mesopotamian civilizations cultivated the opium poppy (Papaver somniferum). The Sumerians called it the “plant of joy” and recognized its analgesic and sedative properties. Later, Egyptians, Greeks, and Romans used opium in both religious rituals and medical treatments.

2. Spread in the Middle Ages

During the Middle Ages, opium spread through Asia and Europe thanks to Arab trade. During this period, the preparation known as laudanum became popular—a tincture of opium in alcohol widely used as a painkiller, sedative, and remedy for multiple ailments.

3. 19th century: morphine and heroin

In the 19th century, morphine was isolated as a powerful analgesic alkaloid from opium, revolutionizing medicine. Soon after, heroin was synthesized as a derivative initially promoted as a cough treatment and a “safer” alternative to morphine, though its high addictive potential was quickly discovered.

4. 20th century: control and prohibition

During the 20th century, problematic opioid use led many countries to implement laws of control and prohibition. In 1914, for example, the United States passed the Harrison Act, which regulated the sale and distribution of opioids. At the same time, synthetic opioids such as methadone and oxycodone were developed for medical use.

5. 21st century: the opioid crisis

In recent decades, especially in the United States, a public health crisis has erupted related to the overuse and indiscriminate prescription of opioid painkillers. This has caused hundreds of thousands of overdose deaths and sparked debates about the need to balance access to pain treatment with addiction prevention.