Chapter 13  ·  Module 1

Opioid Receptors and the Endogenous Opioid System

Receptor types, signal transduction, endogenous peptides, and tolerance

The Three Classical Opioid Receptors

Mu Receptor

Primary Clinical Target

  • Supraspinal and spinal analgesia
  • Euphoria / reward
  • Respiratory depression
  • Constipation (peripheral)
  • Miosis
  • Physical dependence

Kappa Receptor

Mixed Agonist Target

  • Spinal analgesia
  • Sedation
  • Dysphoria
  • Miosis
  • Target of buprenorphine, nalbuphine, butorphanol

Delta Receptor

Mood and Analgesia

  • Supraspinal and spinal analgesia
  • Mood modulation
  • Enhances mu receptor signaling
  • No approved selective agonist

Gi/Go Signal Transduction: Three Downstream Effects

Agonist Binds Receptor

Gi/Go protein activated

→

Effect 1

Inhibit adenylyl cyclase
cyclic AMP decreases

+

Effect 2

Open K+ channels
hyperpolarization

+

Effect 3

Close Ca²+ channels
less neurotransmitter release

→

Net Result

Reduced neuronal excitability
Analgesia

Endogenous Opioid Peptide Families

Peptide Family Precursor Protein Receptor Preference Key Physiological Role
Beta-endorphin Pro-opiomelanocortin Mu, delta Stress-induced analgesia; exercise-related mood elevation
Enkephalins Proenkephalin Delta, mu Spinal dorsal horn pain modulation; short-range neurotransmitter
Dynorphins Prodynorphin Kappa Stress response; dysphoria in limbic circuits

Tolerance, Dependence, and Addiction: Key Distinctions

Concept

Tolerance

  • Reduced response at same dose
  • Develops to: analgesia, euphoria, sedation, respiratory depression, nausea
  • Does NOT develop to constipation or miosis

Concept

Physical Dependence

  • Neuroadaptation requiring opioid for normal function
  • Withdrawal on abrupt cessation
  • Mechanism: cyclic AMP rebound from upregulated adenylyl cyclase
  • Does NOT equal addiction

Concept

Addiction (Opioid Use Disorder)

  • Compulsive use despite harm
  • Mesolimbic dopamine pathway (ventral tegmental area to nucleus accumbens)
  • Faster delivery = greater reward signal
  • Distinct from dependence

Clinical Rule: What Tolerizes and What Does Not

Tolerance develops to analgesia, euphoria, sedation, nausea, and respiratory depression. Tolerance does not develop to constipation or miosis. A patient on long-term opioid therapy will retain pinpoint pupils and persistent constipation regardless of how long they have been on the medication.