Activation of mu-opioid receptors by fentanyl generally leads to which downstream effect?

• A. Increased intracellular calcium and neurotransmitter release
• B. Opening of calcium channels
• C. Potassium channel opening and reduced neuronal excitability
• D. Inhibition of G-protein signaling

Answer: (C)

Mu-opioid receptor activation signals through Gi/o proteins, which dampen neuronal signaling. This leads to two main downstream effects: opening of potassium channels (GIRK channels) that hyperpolarize the neuron and reduce excitability, and inhibition of voltage-gated calcium channels that decreases calcium influx and thus lowers neurotransmitter release at synapses. The combination produces less neuronal activity and analgesia. The other options imply increases in calcium or transmitter release, or incorrect G-protein signaling, which do not fit how mu-opioid receptors work.