Opioid Receptor Pharmacology
Opioid receptor types, endogenous opioid peptides, and the pharmacology of opioid agonists, antagonists, and partial agonists.
## Endogenous Opioid Peptides
Three families of endogenous opioid peptides arise from distinct precursor proteins:
- **Endorphins** (from POMC) -- beta-endorphin preferentially binds mu receptors; released during stress, exercise, and pain
- **Enkephalins** (from proenkephalin) -- met- and leu-enkephalin bind delta and mu receptors; widespread CNS distribution
- **Dynorphins** (from prodynorphin) -- prefer kappa receptors; modulate pain and mood (often dysphoric)
## Opioid Receptor Subtypes
All opioid receptors are Gi/Go-coupled GPCRs that inhibit adenylyl cyclase, open K+ channels (hyperpolarization), and close Ca2+ channels (reduced neurotransmitter release).
| Receptor | Effects | Clinical Relevance |
|----------|---------|-------------------|
| Mu (MOR) | Analgesia, euphoria, respiratory depression, miosis, constipation | Target of morphine, fentanyl, methadone |
| Kappa (KOR) | Analgesia, dysphoria, sedation, diuresis | Pentazocine; kappa antagonists for depression |
| Delta (DOR) | Analgesia, mood modulation | Under investigation; limited clinical agents |
## Key Drug Classes
- **Full agonists** -- morphine, fentanyl, oxycodone, methadone; dose-dependent respiratory depression is the primary cause of overdose death
- **Partial agonists** -- buprenorphine has a ceiling effect on respiratory depression; used for opioid use disorder (OUD) and pain
- **Mixed agonist-antagonists** -- pentazocine (kappa agonist, mu partial agonist); can precipitate withdrawal in opioid-dependent patients
- **Antagonists** -- naloxone (IV/IM/nasal, short-acting) reverses overdose; naltrexone (oral/IM depot, long-acting) for OUD and alcohol use disorder
- **Peripherally restricted antagonists** -- methylnaltrexone, naloxegol treat opioid-induced constipation without reversing central analgesia
## Tolerance and Dependence
Chronic mu receptor activation leads to receptor desensitization and downregulation. Tolerance develops to analgesia, euphoria, and sedation but not to constipation and miosis. Physical dependence manifests as withdrawal syndrome upon abrupt cessation.
## Key Takeaways
- Mu receptor activation mediates both therapeutic analgesia and dangerous respiratory depression
- Buprenorphine's partial agonism provides a ceiling on respiratory depression, making it safer for OUD treatment
- Naloxone reversal of opioid overdose is life-saving but short-acting; re-sedation monitoring is essential
- Tolerance develops unevenly across opioid effects