Mechanisms Of The Dynorphin/κ Opioid Receptor System-mediated Motor Modulation Of Cognitive Dysfunction In Morphine Withdrawal Mice

BackgroundCognitive dysfunction is a common feature of substance use disorders(SUD)and other psychiatric disorders.It now poses a significant health problem and public health burden to society.While there are a variety of treatments for cognitive impairment,exercise is widely used to prevent and treat various disorders as more emphasis is now placed on managing the overall quality of life of patients.A large body of experimental and medical data has shown that regular participation in exercise significantly reduces the likelihood of developing cognitive impairment.Exercise can also prevent and promote cognitive development in many ways,including the production and release of brain-derived neurotrophic factors,appetite hormone,irisin,and endogenous opioid peptides.EEG studies on exercise have also found that moderate-intensity acute aerobic exercise is effective in improving impaired inhibition in methamphetamine addicts,and that this improvement is strongly associated with activation of the prefrontal cortex.Since the prefrontal cortex contains opioid peptides and opioid receptors,and the activity of prefrontal cortex cells may be related to the activation of opioid receptors.A recent interesting study found that acute morphine withdrawal can disrupt cognitive function by inducing the release of prodynorphin in the medial prefrontal cortex(mPFC)and activating local κ opioid receptors(KORs),suggesting that prodynorphin plays an important role in cognitive impairment after chronic drug use.Together with the fact that opioid peptides and their receptors are also distributed in hippocampal brain regions associated with learning memory,we thus hypothesize that endogenous opioid peptides may be involved in the process of exercise prevention and amelioration in patients with drug withdrawal.However,it is unclear whether exercise affects morphine withdrawal-induced cognitive dysfunction via endogenous opioid peptides.The present study investigated the physiological mechanisms by which exercise prevents and ameliorates morphine withdrawal-induced cognitive impairment.ObjectiveTo investigate whether aerobic exercise can modulate morphine withdrawal-induced cognitive impairment in mice and its possible mechanisms.MethodsThe experiment of this study consisted of two parts.The experimental study was conducted on 8-9 weeks old male C57BL/6 mice,based on the construction of a morphine withdrawal mouse model,with aerobic exercise interventions before and after the construction,respectively.After performing behavioral tests related to the detection of cognition,two brain regions(hippocampus and medial prefrontal cortex)related to cognition were taken as the material for subsequent molecular biochemical experiments.The first part of the experiment was aimed at whether aerobic exercise could prevent cognitive deficits induced by morphine withdrawal in mice,and the exercise intervention preceded the construction of a morphine withdrawal mouse model.The open field experiment,the temporal memory experiment,and the spontaneous alternating Y-maze experiment were used to assess the cognitive status of the mice.Brain tissue from the hippocampus and medial prefrontal cortex was taken,and protein blotting and immunofluorescence staining experiments were used to detect whether cognitive-related brain regions were altered in morphine-withdrawn mice.The second part of the experiment was aimed at whether aerobic exercise could improve the cognitive impairment induced by morphine withdrawal mice,and the intervention of exercise was constructed after the morphine withdrawal mouse model.The open field experiment,the temporal memory experiment,and the spontaneous alternating Y-maze experiment were used to assess the cognitive status of the mice.Brain tissues from the hippocampus and medial prefrontal cortex were taken separately,and protein blotting and immunofluorescence staining experiments were used to detect whether cognitive-related brain regions were altered in morphine-withdrawn mice.Results1.Compared to the WT group,mice triggered cognitive impairment after acute morphine withdrawal,whereas aerobic exercise effectively prevented the development of cognitive impairment after acute morphine withdrawal.2.WB and immunofluorescence staining showed that PDYN protein expression was increased in the hippocampus of the MW group compared with the WT group(P< 0.05),whereas PDYN protein expression was decreased in the hippocampal brain regions of the EMW group compared with the MW group(P < 0.05),but there were no differences in the expression of related proteins in POMC,OPRK1,MOR,and mPFC brain regions in the hippocampus.3.Compared to the WT group,mice triggered cognitive deficits after acute morphine withdrawal,while aerobic exercise effectively ameliorated the cognitive deficits caused by acute morphine withdrawal.4.WB and immunofluorescence staining showed that OPRK1 protein expression in the mPFC brain region was increased in the MW group compared with the WT group(P < 0.05),whereas OPRK1 protein expression in the mPFC brain region was decreased in the MWE group compared with the MW group(P < 0.05),but there were no differences in the expression of PDYN,POMC,MOR,and related proteins in the hippocampus in the mPFC.ConclusionIn the present study,we demonstrated that moderate-intensity aerobic exercise is effective in preventing and ameliorating the mechanisms by which morphine withdrawal triggers cognitive deficits: prevention by reducing the hippocampal region of prodynorphin and amelioration by reducing the κ opioid receptors of mPFC prodynorphin.