What is the mechanism of action of opioids?

Mechanism of Action of Opioids

Opioids primarily exert their analgesic effects through agonist activity at mu opioid receptors (MORs), with some compounds also binding to delta and kappa opioid receptors to contribute to pain relief. 1, 2

Primary Receptor Interactions

• Opioids bind to four types of opioid receptors: mu (MOR), delta (DOP), kappa (KOP), and nociceptin/orphanin FQ (NOP), with MOR being the most clinically relevant for analgesia 1, 3
• The mu opioid receptor is the primary target for most clinically used opioids, with no ceiling effect for analgesia when acting as full agonists 2
• Opioid receptors are G-protein coupled receptors that cause cellular hyperpolarization when activated by agonists 4

Anatomical Distribution of Opioid Receptors

• MORs are highly expressed in brain regions that regulate pain perception including the periaqueductal gray, thalamus, cingulate cortex, and insula 1
• MORs are also found in brain regions associated with reward (ventral tegmental area, nucleus accumbens), explaining their addictive potential 1
• Opioid receptors are located throughout the central nervous system (brain and spinal cord) and in peripheral tissues 1, 5
• The brainstem respiratory center (pre-Bötzinger complex) contains MORs, which explains opioid-induced respiratory depression 1

Cellular Mechanisms of Action

• At the cellular level, opioids inhibit presynaptic N-type voltage-dependent calcium channels and to a lesser extent P/Q-type channels, reducing neurotransmitter release 6
• Opioids reduce the rate of miniature EPSCs in a dose-dependent manner, indicating effects on spontaneous neurotransmitter release 6
• Opioids differ from other analgesics by reducing pain perception rather than antagonizing the transmission of pain signals 1
• Although sensory transmission remains intact, the subjective interpretation of pain is altered 1

Systemic Effects of Opioid Receptor Activation

• Central Nervous System Effects:

  • Respiratory depression through direct action on brainstem respiratory centers 2
  • Miosis (pupillary constriction), even in total darkness 2
  • Sedation and euphoria 1

• Gastrointestinal Effects:

  • Reduced motility with increased smooth muscle tone in the stomach and duodenum 2
  • Decreased propulsive contractions in the small intestine 2
  • Constipation due to decreased propulsive peristaltic waves and increased tone in the colon 2
  • Spasm of sphincter of Oddi and reduced biliary/pancreatic secretions 2

• Cardiovascular Effects:

  • Peripheral vasodilation which may cause orthostatic hypotension 2
  • Manifestations of histamine release including pruritus, flushing, and sweating 2

• Endocrine Effects:

  • Inhibition of adrenocorticotropic hormone, cortisol, and luteinizing hormone 2
  • Stimulation of prolactin, growth hormone, insulin, and glucagon secretion 2
  • Potential hypogonadism with chronic use 2

Pharmacokinetic Considerations

• Opioids vary in binding affinity and selectivity for different opioid receptors, affecting their potency 1
• Pharmacokinetics and bioavailability determine the rapidity and duration of action 1
• Route of administration affects onset of action - rapid delivery to the brain (e.g., intravenous, intranasal) produces stronger reward and addiction potential 1

Tolerance, Dependence, and Hyperalgesia

• With repeated administration, both physical and perceptual effects diminish, leading to tolerance 1
• Tolerance to analgesia develops faster than tolerance to respiratory depression, increasing overdose risk 1
• Physical dependence manifests as withdrawal symptoms upon abrupt discontinuation 1
• Opioid-induced hyperalgesia can develop even after a few administrations 1
• These effects involve molecular and circuit-level adaptations in opioid receptors and their intracellular signaling cascades 1

Peripheral Opioid Actions

• Peripheral opioid receptors contribute to analgesia, particularly in inflammatory conditions 5, 3
• Immune cells express opioid receptors and can release endogenous opioid peptides that activate neuronal opioid receptors 3
• Peripherally-acting opioids may provide analgesia with fewer central nervous system side effects 5

Understanding the complex mechanisms of opioid action helps explain both their therapeutic efficacy and their significant side effect profile, which must be carefully considered when prescribing these medications.