Mechanism of Action of Opioids:

  1. Binding to Opioid Receptors: Opioids, such as morphine or synthetic opioids, bind to specific opioid receptors in the central nervous system (CNS) and peripheral tissues. The main types of opioid receptors include mu (μ), kappa (κ), and delta (δ) receptors.
  2. Activation of Opioid Receptors: When opioids bind to these receptors, they activate them, leading to a series of intracellular events.
  3. Intracellular G Protein Activation: Opioid receptors are coupled to intracellular guanine (G) proteins. Upon activation by opioid agonists, the receptor undergoes a conformational change, activating the G protein bound to its intracellular domain.
  4. G Protein Activation: The G protein exchanges guanine diphosphate (GDP) for guanine triphosphate (GTP) and splits into two active subunits.
  5. Inhibition of Adenylate Cyclase: One of the subunits inhibits adenylate cyclase, an enzyme responsible for producing cyclic adenosine monophosphate (cAMP). This results in a decrease in cAMP levels.
  6. Modulation of Ion Channels: Opioid receptors also modulate ion channels. This includes:
  • Increased Potassium Conductance: Opioid activation leads to increased potassium conductance, causing hyperpolarization of the neuron membrane, making it less likely to generate an action potential.
  • Calcium Channel Inactivation: Calcium channels are inhibited, reducing the influx of calcium ions into the neuron.
  • Opening of Inward-Flowing Potassium Channels: Opioids can also open inward-flowing potassium channels, further contributing to hyperpolarization.
  1. Decreased Neurotransmitter Release: These intracellular events collectively result in decreased neurotransmitter release from the presynaptic neuron. Neurotransmitters like acetylcholine, dopamine, norepinephrine, and substance P are affected. This reduction in neurotransmission is a key factor in opioid-induced analgesia (pain relief).
  2. Modulation of Phosphoinositide Signaling: Opioid receptors can modulate the phosphoinositide-signaling cascade and phospholipase C, influencing various cellular processes.
  3. Suppression of Substance P Release: Opioid receptor-mediated suppression of calcium ion influx leads to the suppression of neurotransmitter release, particularly substance P, in many neuronal systems.
  4. Hyperpolarization and Reduced Neuronal Activity: The combined effects of increased potassium conductance, calcium channel inactivation, and the opening of potassium channels result in hyperpolarization of the neuron, making it less excitable and reducing neuronal activity.
  5. Modulation of N-Methyl-D-Aspartate (NMDA) Receptors: Opioid receptors may also regulate the functions of other ion channels, including excitatory postsynaptic currents evoked by NMDA receptors.
  6. Overall Effect: The principal effect of opioid receptor activation is a decrease in neurotransmission, leading to pain relief and other central and peripheral effects associated with opioid use.

Understanding this step-by-step mechanism of action is essential for comprehending how opioids exert their analgesic effects and how they can also lead to side effects such as respiratory depression and euphoria.


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