Delta Opioid Receptors within the Cortico‐Thalamic Circuitry Underlie Hyperactivity Induced by High‐Dose Morphine

Morphine activates the excitatory cingulate cortex–intermediate rostrocaudal division of zona incerta (Cg‐ZIm) pathway to drive hyperlocomotion in mice. Inhibiting the Cg‐ZIm pathway attenuates both acute and chronic morphine‐induced hyperlocomotion, while its activation mimics morphine's motor effects. Furthermore, delta‐opioid receptors (DOR) within the ZIm are required for this response, revealing a key circuit and receptor mechanism underlying high‐dose morphine‐induced psychomotor activation. Abstract Hyperactivity is a well‐documented neurobehavioral effect of morphine and other opioid drugs, predominantly observed in rodent models, yet the neural circuits and molecular mechanisms underlying this effect remain elusive. In this study, an excitatory projection from the cingulate cortex (Cg) to the intermediate rostrocaudal division of zona incerta (ZIm) is revealed that is activated by morphine in mice. Chemogenetic inhibition of the Cg‐ZIm pathway decreased high‐dose (10–15mg kg−1) morphine‐induced hyperlocomotion without affecting its analgesic effects. Activation of this pathway faithfully reproduced the motor effect of morphine. Furthermore, high‐dose morphine‐induced hyperlocomotion is quickly attenuated by microinjecting delta‐opioid receptor (DOR) antagonists into the ZI, which is not observed following the targeted knockout of the DOR in Cg‐projecting ZI neurons, indicating a postsynaptic DOR‐mediated mechanism. In summary, these findings identify the critical role of the DOR within the Cg‐ZIm circuit in the psychomotor properties of morphine. This work sheds light on potential targets within the Cg‐ZIm pathway for mitigating the undesired psychomotor effects of morphine and thereby optimizing its clinical outcomes. Morphine activates the excitatory cingulate cortex–intermediate rostrocaudal division of zona incerta (Cg-ZIm) pathway to drive hyperlocomotion in mice. Inhibiting the Cg-ZIm pathway attenuates both acute and chronic morphine-induced hyperlocomotion, while its activation mimics morphine's motor effects. Furthermore, delta-opioid receptors (DOR) within the ZIm are required for this response, revealing a key circuit and receptor mechanism underlying high-dose morphine-induced psychomotor activation. Abstract Hyperactivity is a well-documented neurobehavioral effect of morphine and other opioid drugs, predominantly observed in rodent models, yet the neural circuits and molecular mechanisms underlying this effect remain elusive. In this study, an excitatory projection from the cingulate cortex (Cg) to the intermediate rostrocaudal division of zona incerta (ZIm) is revealed that is activated by morphine in mice. Chemogenetic inhibition of the Cg-ZIm pathway decreased high-dose (10–15mg kg −1 ) morphine-induced hyperlocomotion without affecting its analgesic effects. Activation of this pathway faithfully reproduced the motor effect of morphine. Furthermore, high-dose morphine-induced hyperlocomotion is quickly attenuated by microinjecting delta-opioid receptor (DOR) antagonists into the ZI, which is not observed following the targeted knockout of the DOR in Cg-projecting ZI neurons, indicating a postsynaptic DOR-mediated mechanism. In summary, these findings identify the critical role of the DOR within the Cg-ZIm circuit in the psychomotor properties of morphine. This work sheds light on potential targets within the Cg-ZIm pathway for mitigating the undesired psychomotor effects of morphine and thereby optimizing its clinical outcomes. Advanced Science, EarlyView.