How do mu-opioid receptor agonists produce analgesia at the cellular level?

• A. They increase neurotransmitter release by calcium influx
• B. They inhibit voltage-gated calcium channels, open potassium channels, and decrease cAMP signaling
• C. They activate NMDA receptors to enhance signaling
• D. They block sodium channels in nociceptors

Answer: (B)

Activation of mu-opioid receptors couples to Gi/o proteins, which switch off adenylyl cyclase and lower cAMP levels, reducing PKA activity. This signaling also directly inhibits voltage-gated calcium channels and, via the Gβγ subunits, opens GIRK potassium channels. The combination short-circuits excitatory neurotransmitter release from nociceptive terminals by limiting calcium entry, and it hyperpolarizes the postsynaptic neuron, making it less likely to fire. Together, these presynaptic and postsynaptic effects dampen pain signaling in the spinal cord and brain, producing analgesia.

In contrast, increasing calcium influx would enhance neurotransmitter release; activating NMDA receptors would promote excitation rather than analgesia; and blocking sodium channels in nociceptors is more characteristic of local anesthetics than opioid analgesia.