Chronic opioid use activates dynorphin–KOR signaling → dysphoria, stress-induced craving (Carlezon & Krystal, 2016).
KOR antagonists (e.g., aticaprant, JNJ-67953964) block this pathway, restoring reward responsivity.
Reduce negative affect, anhedonia, and relapse risk.
Represents a shift from blocking pleasureto relieving suffering.
KORs: concentrated in amygdala, hypothalamus, and NAc shell → mediate dysphoria, stress, and anti-reward.
These agents quiet the anti-reward system—the biology of hopelessness itself. Is there a moral or ethical dimension in the targets of drug development? Does this get closer to the heart of the problem in addiction?
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