Release of endogenous dynorphin opioids in the prefrontal cortex disrupts cognition

Abstract

Following repeated opioid use, some dependent individuals experience persistent cognitive deficits that contribute to relapse of drug-taking behaviors, and one component of this response may be mediated by the endogenous dynorphin/kappa opioid system in neocortex. In C57BL/6 male mice, we find that acute morphine withdrawal evokes dynorphin release in the medial prefrontal cortex (PFC) and disrupts cognitive function by activation of local kappa opioid receptors (KORs). Immunohistochemical analyses using a phospho-KOR antibody confirmed that both withdrawal-induced and optically evoked dynorphin release activated KOR in PFC. Using a genetically encoded sensor based on inert KOR (kLight1.2a), we revealed the in vivo dynamics of endogenous dynorphin release in the PFC. Local activation of KOR in PFC produced multi-phasic disruptions of memory processing in an operant-delayed alternation behavioral task, which manifest as reductions in response number and accuracy during early and late phases of an operant session. Local pretreatment in PFC with the selective KOR antagonist norbinaltorphimine (norBNI) blocked the disruptive effect of systemic KOR activation during both early and late phases of the session. The early, but not late phase disruption was blocked by viral excision of PFC KORs, suggesting an anatomically dissociable contribution of pre-and postsynaptic KORs. Naloxone-precipitated withdrawal in morphine-dependent mice or optical stimulation of pdyn Cre neurons using Channelrhodopsin-2 disrupted delayed alternation performance, and the dynorphin-induced effect was blocked by local norBNI. Our findings describe a mechanism for control of cortical function during opioid dependence and suggest that KOR antagonism could promote abstinence.

Region Specificity in Endogenous Opioid Peptides and Mu-opioid Receptor Gene Expression in Rat Brain Areas Involved in Addiction After Frequent Morphine Treatment

“…Based on the data mentioned above, the present results may demonstrate that the frequent injection of morphine and the subsequent overflow of dopamine in the target areas may gradually increase Pdyn expression, which, in turn, increases Penk expression via dopamine release re-duction and D2 dopamine receptor mechanism. The release of endogenous dynorphins in the prefrontal cortex disrupts cognition (55). Therefore, the increased expression of Pdyn in the PFC may be a possible explanation for cognitive impairments in morphine-dependent animals reported elsewhere (18,56).…”

The Kappa Opioid Receptor: A Promising Therapeutic Target for Multiple Pathologies

“…In contrast, other studies have shown that KOR agonists disrupt cognition. Abraham et al (2021) found that dynorphin-induced KOR activation in the medial prefrontal cortex disrupted cognition in mice undergoing acute morphine withdrawal. Furthermore, U50,488 has been shown to inhibit novel object recognition in mice ( Paris et al, 2011 ), and SalA reduced motivation and increased processing deficits in rats that were made to complete a multi-choice serial reaction time task ( Nemeth et al, 2010 ).…”

Three Mutations Convert the Selectivity of a Protein Sensor from Nicotinic Agonists to S-methadone for Use in Cells, Organelles, and Biofluids

“…Along with other sensors of opioid signaling 11,27 , this study establishes the first genetically encoded fluorescent protein biosensor for an opioid drug, enabling real-time quantification. Furthermore, the enantioselectivity encourages biosensor development to investigate "chiral switching" of other drugs where a single enantiomer substitutes a clinically used racemate 28 .…”