Opioidergic pain relief in humans is mediated by beta and high-gamma modulation in limbic regions

The neurophysiological mechanisms underlying opioid analgesia remain poorly understood, limiting the development of non-addictive alternatives. Fentanyl and hydromorphone were administered to patients experiencing semi-chronic, clinically relevant pain following surgical implantation of intracranial electrodes for seizure localization. Opioids suppressed beta oscillations in lateral amygdala and ventral and dorsolateral prefrontal cortices, while increasing beta power in the medial amygdala and hippocampus. High-gamma amplitude was suppressed in the insula and lateral amygdala, and increased in the cingulate cortex and hippocampus. The magnitude of beta suppression in the ventral prefrontal cortex and beta enhancement in the medial amygdala and hippocampus, as well as high-gamma suppression in the insula, were positively correlated with pain relief in response to a constant dose. These findings identify electrophysiological events in a limbic network that may mediate opioidergic analgesia via nociceptive gating and reduced affective salience of pain, offering insights into the neural basis of pain relief and potential biomarkers for the development of non-addictive opioid alternatives.