The protective role of µ- and δ-opioid receptor blockage on memory deficits after mild traumatic brain injury is dependent on preexisting high endogenous opioid tone.

Mild traumatic brain injury (mTBI) causes deficits in memory formation and retrieval by disrupting the balance in synaptic excitability and inhibition. The pre-trauma endogenous opioid tone could influence the severity of post-trauma cognitive deficits. Thus, the current investigation aimed to evaluate how post-mTBI adaptations in opioid receptor subtype signaling affect the severity of memory dysfunction depending on the endogenous opioid tone. For this purpose, we utilized adult male mice divergently bred for high (HA) and low (LA) endogenous opioid system activity. Mild traumatic brain injury was induced by a mechanical impact to the temple. Memory formation and retrieval were assessed in the Morris Water Maze and Novel Object Recognition tasks. Contribution of opioid µ-, δ- and κ- receptor subtypes was studied by administration of selective opioid receptor antagonists - cyprodime, naltrindole or nor-binaltorphimine prior to mTBI. Expression and activation of opioid receptor subtypes were quantified by qPCR and the [35S]GTPγS assay. LA mice experienced more severe post-mTBI spatial learning deficits accompanied by diminished signaling from all three receptor subtypes in the hippocampus. Alterations in µ- or δ-opioid receptor signaling in the medial prefrontal cortex did not differentiate the lines in terms of recognition memory or spatial memory retrieval. In HA mice, both spatial memory formation and retrieval were improved with selective µ- opioid receptor blockage, while restoration of recognition memory was related to either µ- or δ-opioid receptor inhibition. In conclusion, bidirectional selection for the endogenous opioid tone creates line-dependent alterations in opioid receptor subtype-mediated regulation of memory processes.