As addiction progresses:
-  Anti-reward system activates stress pathways mediated by increases in dynorphins, corticotrophin-releasing factor (CRF), and noradrenaline 
- Excess activation of dopamine receptors upregulate the production of dynorphins, which leads to negative feedback on dopamine release 
- Results in the mesolimbic system becoming hypodopaminergic giving rise to anhedonia and tolerance to the euphoric effects of drugs
- Dominance of the anti-reward pathway explains the negative emotions (malaise and dysphoria) experienced during withdrawal 

Rutgers University

Reward and Anti-Reward Pathways 

Kakko J, Alho H, Baldacchino A, Molina R, Nava FA and Shaya G
 2019) Craving in Opioid Use Disorder: From Neurobiology to Clinical Practice.Front. Psychiatry 10:592. doi: 10.3389/fpsyt.2019.00592

Craving in Opioid Use Disorder: From Neurobiology to Clinical Practice

During acute intoxication:
- Mesolimbic pathway becomes activated and dopamine is upregulated
- This leads to positive reinforcing symptoms like euphoria 
- Other neurotransmitter systems in positive reinforcement include endogenous opioids, γ-aminobutyric acid, glutamate, neuropeptide Y, and
glucocorticoids 
- The frontal cortex function is important in the effects of craving and inhibitory behavioral control 

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