Drug abuse results in over 500,000 deaths worldwide annually. Among these casualties, nearly 115,000 are attributed to opioid overdose. While several individuals avert this fate through deaddiction, they often relapse owing to anxiety, depression and other negative emotional effects accompanying withdrawal. Now, scientists have discovered a specific brain circuit involved in opioid addiction and withdrawal, offering hope for better treatments.

Through a new study, scientists from the Texas A&M University School of Medicine have uncovered a neural pathway that characterizes how fentanyl, a synthetic opioid, affects the brain. Particularly, they learnt how certain neurons in the striatum–the region controlling voluntary behaviours–promoted drug relapse. The findings of the animal study were published in the journal Cell Reports.

"The effect on the striatonigral pathways induces a hypodopaminergic state, which may underlie the mechanism of anxiety-like behaviours during acute opioid withdrawal. These results provide valuable insights into the mechanisms underlying opioid-induced negative emotional states that drive relapse," the authors wrote.

Mediation of Addiction and Withdrawal

Drug Addiction (Representational Picture)Creative Commons

Opioids are a class of drugs that function as analgesics (also known as painkillers) by interacting with opioid receptors on neurons. While they alleviate pain, opioids are also used to treat cough, diarrhea, and other conditions. However, these substances make one experience euphoria, leading to their misuse as narcotics. Even under close supervision, opioids can be dependence-forming and result in addiction.

Some of the commonly prescribed—and abused—opioids are codeine, fentanyl, hydrocodone, morphine, and oxycodone. Opioid addiction is primarily mediated by mu-opioid receptors (MORs). These receptors are expressed in the midbrain (the topmost part of the brainstem) and the striatum (in the forebrain) on a neuron known as direct pathway medium spiny neurons (dMSNs). These neurons play a key role in regulating motor output and goal-directed behaviours.

In previous studies, the team demonstrated that dMSNs regulate "go" functions within the brain that initiate drug-seeking behaviours. The striatum consists of two sub-compartments: patch and matrix. MOR-expressing dMSNs are mainly concentrated in the patch compartment and their role in decision-making and emotional processing has been widely researched.

Unlocking Mechanisms Affecting Withdrawal

Drugs (Representational Picture)Pxhere

Through the current mice study, the authors aimed to ascertain how withdrawal from chronic opioid exposure modifies the activity of dMSNs in the patch region and their outputs to produce negative emotional states which may lead to relapse.

It was learnt that the activity of dMSNs in the striatum is amplified by fentanyl. Also, during the initial phases of withdrawal, inhibitory signals transmitted by these dMSNs to downstream targets–such as dopaminergic neurons–were substantially elevated.

The role of dopaminergic neurons is crucial in addiction: they regulate motivation, rewarding behaviour and emotions. According to the team, it is likely that the increased suppression of dopaminergic neurons promotes negative emotions that emerge during chronic fentanyl withdrawal–it was found that the inhibition of these dMSNs reduced anxiety-like behaviours and withdrawal symptoms.

The findings offer novel insights into the mechanism controlling negative emotional states induced by opioids and provide new avenues for treating opioid-caused disorders. Through the reduction of negative emotional states accompanying withdrawal, the risk of relapse may be potentially reduced and lives saved, the authors believe.