## Opioid Receptor Pharmacology **Key Point:** The mu (μ) receptor is the primary target for all clinically used opioids and is responsible for both therapeutic and addictive properties. ### Receptor Subtypes and Their Functions | Receptor | Location | Primary Effects | Role in Addiction | |----------|----------|-----------------|-------------------| | **Mu (μ)** | Periaqueductal gray, nucleus accumbens, locus coeruleus | Analgesia, euphoria, respiratory depression, miosis | **Primary driver of dependence** | | **Delta (δ)** | Limbic system, spinal cord | Analgesia, dysphoria | Minimal addiction potential | | **Kappa (κ)** | Hypothalamus, brainstem | Analgesia, dysphoria, sedation | Aversive effects; may reduce craving | | **Nociceptin** | Spinal cord, brain | Hyperalgesia modulation | Not involved in addiction | **High-Yield:** Mu receptor activation in the ventral tegmental area (VTA) and nucleus accumbens triggers dopamine release, which is the neurobiological basis of reward and reinforcement in opioid use disorder. **Clinical Pearl:** All FDA-approved medications for opioid use disorder (methadone, buprenorphine, naltrexone) work by modulating mu receptor signaling — methadone and buprenorphine are mu agonists; naltrexone is a mu antagonist. ### Mechanism of Dependence 1. Mu receptor activation → dopamine surge in nucleus accumbens 2. Chronic use → receptor downregulation and tolerance 3. Withdrawal → unopposed inhibitory tone from locus coeruleus 4. Craving and relapse driven by conditioned associations with mu receptor activation [cite:Harrison 21e Ch 394]
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