Activation of fentanyl at the mu-opioid receptor leads to which downstream effect?

• A. Direct activation of NMDA receptors
• B. Conformational shift of the mu-opioid receptor with G protein subunits dissociating and downstream inhibition of calcium, opening of potassium channels, and silencing nociceptive signaling
• C. Increased calcium influx and enhanced neurotransmitter release
• D. Inhibition of potassium channels leading to increased neuronal excitability

Answer: (B)

Activating the mu-opioid receptor triggers a Gi/Go protein–coupled signaling cascade. When fentanyl binds, the receptor undergoes a conformational change and the G proteins dissociate into subunits. The beta-gamma subunits inhibit voltage-gated calcium channels, reducing calcium influx and neurotransmitter release, while they also promote opening of potassium channels, causing the neuron to hyperpolarize. This combination dampens nociceptive signaling and produces analgesia. That’s why this option best captures the downstream effects.

Direct activation of NMDA receptors is not how mu-opioid signaling works, and would increase excitation rather than silence signaling. Increased calcium influx and enhanced neurotransmitter release contradict the GPCR actions described. Inhibition of potassium channels would raise excitability, which is the opposite of the mu-opioid–mediated effect.