A neural circuit from paratenial thalamic nucleus to anterior cingulate cortex for the regulation of opioid-induced hyperalgesia in male rats

Prolonged use of opioids can lead to increased sensitivity to painful stimuli, a condition referred to as opioid-induced hyperalgesia (OIH). However, the mechanisms underlying this contradictory situation remain unclear. This study elucidates the pivotal role of the paratenial thalamic nucleus (PT)-anterior cingulate cortex (ACC) neuronal circuit in the development of OIH in male rats. Immunofluorescence and electrophysiology experiments demonstrated aberrant activation of PT glutamatergic neurons (PT^Glu) in rats with OIH. Optogenetic or chemogenetic activation of the PT^Glu-ACC circuit aggravates mechanical and thermal hyperalgesia. Conversely, the inhibition of neuronal circuits showed analgesic effects. Additionally, PT^Glu neurons project to both ACC pyramidal neurons and interneurons. Moreover, OIH affects the function of the ACC microcircuit, leading to decreased feedforward inhibition and an inhibitory/excitatory (I/E) imbalance in ACC pyramidal neurons. In conclusion, our findings highlighted the role of the PT^Glu-ACC neuronal circuit in the development of opioid-induced hyperalgesia, suggesting that this circuit is a promising therapeutic target for addressing the side effects of opioids.