Opioids

Question 1

What is the main receptor involved in opioid use disorder(OUD)?

Answer 1

The Mu-opiod receptor (MOR) - Heroin and fentanyl are full MOR agonists and have fast uptake for a highly rewarding effect

Question 2

What are the brain developmental factors which contribute to OUD?

Answer 2

• During adolescence reward and emotion circuits develop faster than that for executive function hence causing an imbalance of the systems linked to experimentation, reward-seeking and self-regulation - which may lead to drug use.
• Early drug use may impair the development of the PFC
• Effect of social stressor/ adverse social environments on brain development increase vulnerability to opiod use and OUD

Question 3

Which brain circuitry is involved in OUD?

Answer 3

Reward, emotion and executive control circuitry

Question 4

What occurs during drug induced reward signalling?

Answer 4

• Supraphysiologic release of dopamine by the ventral tegmental area (VTA).
• It binds to the low-affinity D1 receptors an the ventral and dorsal striatum
• Stimulates cAMP signalling associated with euphoria and pleasure
• Conditioning (learned association between drug effects and situation)

Question 5

What occurs during drug induced conditioning in addiction?

Answer 5

• Repeated drug use - cue conditioning - exposure to cue triggers the firing of the dopamine neurone - drives motivation to obtain drug reinforcer.
• Previously neutral stimuli acquire incentive salience
• Conditioning triggers synaptic changes in the glutamate receptors (NMDA and AMPA), which enhances glutamate signalling, which then strengthens circuits involved in habit formation and compulsive response to drugs.

Question 6

How does the Emotion circuitry play a role in OUD?

Answer 6

• Negative emotional states arise from withdrawal symptoms - hence drug taking as negative reinforcement
• Extended amygdala and stress related neurotransmitters (CRF, norepinephrine, dynorphin) lead to distress and irritability
• Reward prediction errors reduce the dopamine in the VTA via the lateral habenula and hence negative emotional states are triggered and maintained

Question 7

What leads to impairments of executive function in patients with OUD?

Answer 7

• Drug-induced down regulation of D2R in striatum is associated with reduced PFC function
• Reduced function of PFC leads to impaired decision making, lack of self-regulation, poor inhibitory control and difficulties with working memory.

Question 8

Treatments?

Answer 8

• Medically supervised withdrawal
• Ongoing outpatient treatment using drugs of substitution:
• Methadone
• Buprenorphine
• Naltrexone
• NIBS (still in experimental phase)

Question 9

Which drug is used to treat overdose?

Answer 9

Naloxone