PPA Module 2b Lecture 2.11

Introduction to Opioid Peptides

  • Overview of endogenous opioids and opioid system mechanisms.

Opioid Receptors

  • Three main opioid receptors:
    • Mu (μ)
    • Delta (δ)
    • Kappa (κ)
  • Signaling Mechanisms:
    • Each receptor type plays unique roles in physiological responses related to pain and reward.
  • Endogenous Ligands:
    • Endorphins, such as beta endorphins, endomorphins, dynorphins, and enkephalins specifically activate these receptors.
  • Distribution in the Brain:
    • Each receptor and endorphin type has distinct brain pathways influencing pain perception, mood, and behavior.

Opioid Peptide Neurotransmitters

  • Synthesis, Storage, Transport, and Metabolism of Opioid Peptides:
    • Main Opioid Peptide Neurotransmitters:
    • Beta endorphins
    • Endomorphins
    • Dynorphins
    • Enkephalins

1. Beta Endorphins

  • Discovered in 1976.
  • 31 amino acids long, derived from the Proopiomelanocortin (POMC) gene.
  • Receptor Binding:
    • High affinity for mu opioid receptors, lower for delta and kappa.
  • Physiological Role:
    • Potent analgesic, contributes to stress relief and the sensation of the “runner’s high.”
  • Metabolism:
    • Hydrolyzed by various enzymes in the synapse.
  • Distribution:
    • Present in neurons projecting from arcuate nucleus to limbic, brainstem, and spinal cord areas.

2. Enkephalins

  • Discovered in 1975.
  • Precursor is proenkephalin from PEG gene.
  • Types: Met-enkephalins (5 produced) and Leu-enkephalins (1 produced).
  • Receptor Binding:
    • Preferentially binds to delta opioid receptors, also binds mu with less affinity.
  • Physiological Role:
    • Involved in pain modulation and have effects on autonomic functions.
  • Metabolism:
    • Degraded by enkephalinases and aminopeptidases.
  • Distribution:
    • Found in various CNS areas linked to pain perception, emotional regulation, and motor functions.

3. Dynorphins

  • Discovered in 1979.
  • Derived from the prodynorphin gene, includes dynorphin A and dynorphin B.
  • Physiological Role:
    • Both analgesic effects and dysphoria; stimulating kappa receptors leads to negative emotional states.
  • Receptor Binding:
    • High affinity for kappa receptors, less for mu and delta.
  • Metabolism:
    • Enzymatically degraded into shorter active peptides.
  • Distribution:
    • Present in interneurons involved in pain signaling, emotion modulation, and endocrine functions.

4. Endomorphins

  • Discovered in 1997.
  • Shortest endorphins, types I and II yet to have identified precursors.
  • Receptor Binding:
    • High affinity for mu receptors, lower for delta and kappa.
  • Physiological Role:
    • Strong analgesics with minimal reinforcement or respiratory depression.
  • Distribution:
    • Found throughout CNS areas associated with pain control and sedation.

Opioid Agonists and Antagonists

  • Natural and Synthetic Opioid Agonists:
    • Morphine: First isolated opiate, classic analgesic, full mu agonist.
    • Heroin: Synthetic opioid intending to be non-addictive, now known for potent addictive properties.
    • Fentanyl: Synthetic mu agonist, extremely potent, commonly abused; transdermal administration for quick onset.
    • Oxycodone: Developed to be less addictive; often combined with NSAIDs for pain relief.

Therapeutic Uses of Agonists

  • Pain management, cough suppression, and anesthesia in post-operative settings.

Adverse Effects of Opioid Agonists

  • Respiratory Depression:
    • Most dangerous effect; activation of mu receptors in medulla can lead to potentially fatal lows in respiration rate.
  • Euphoria and Addiction:
    • Activation of reward pathways; tolerance develops inconsistently across different opioid effects, increasing overdose risk.
  • Gastrointestinal Effects:
    • Chronic use leads to constipation.

Opioid Antagonists

  • Naloxone: Non-selective antagonist used to reverse opioid overdose.
    • High affinity for mu receptors, fast onset, and short half-life requiring potentially repeated doses.
  • Naltrexone: Oral antagonist used in opioid addiction treatment; longer duration of action, can also counteract alcohol cravings.

Conclusion

  • Understanding the opioid peptide system is crucial for comprehending their role in analgesia, addiction, and therapeutic strategies.
  • Key Points to Remember:
    • Opioid receptors (μ, δ, κ), endogenous agonists, synthetic opioids, therapeutic uses, and adverse effects.
    • Importance of differentiating addictive potential across different opioids and understanding the management of their effects in clinical settings.