N/OFQ alleviates anxiety-like behaviors in nicotine withdrawal-induced rats and its mechanism related to HPA axis and inflammatory factors
AIM:To investigate the ameliorative effect of nociceptin/orphanin(N/OFQ)on anxiety-like be-havior in nicotine(NIC)withdrawal-induced rats and its regulatory mechanisms on the expression of neurotransmitters as-sociated with the hypothalamic-pituitary-adrenal(HPA)axis and inflammatory factors.METHODS:Thirty-two adult male Sprague-Dawley rats were randomly divided into 4 groups:normal control group,NIC withdrawal model group,low-dose N/OFQ treatment group,and high-dose N/OFQ treatment group,with 8 rats in each group.To establish NIC with-drawal model,the rats in the NIC model and N/OFQ treatment groups were subcutaneously injected with NIC(0.4 mg/kg),twice a day for 7 consecutive days followed by 3 days of withdrawal.During the withdrawal period,the rats in the low and high-dose N/OFQ treatment groups received intracerebroventricular injection of N/OFQ(1 nmol or 10 nmol)once per day for 3 consecutive days.Ten minutes after the third administration,all rats underwent open filed(OF)and elevated plus maze(EPM)tests to detect behavioral changes.The serum concentrations of corticotrophin-releasing hormone(CRH),adrenocorticotropic hormone(ACTH),corticosterone(CORT),tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β)and IL-6 were measured by ELISA.The mRNA expression levels of TNF-α,IL-1β and IL-6 in the central nu-cleus of the amygdala(CeA)of the brain were detected by RT-qPCR.Histological changes in neuron morphology in the CA1 region of the hippocampus were observed under a light microscope following hematoxylin and eosin(HE)staining.Norepinephrine(NE)levels in the CeA of the brain were determined by HPLC.The protein expression of tyrosine hydroxy-lase(TH)in the CeA of the brain was detected by Western blot.RESULTS:Compared with the NIC withdrawal model group,rats in the low and high-dose N/OFQ treatment groups showed significant increase in the distance and time spent in the central area of the open field(P<0.05 or P<0.01),as well as significant increase in the number of entries and the per-centage of time spent in the open arms of the EPM(P<0.05 or P<0.01).Furthermore,both low and high-dose N/OFQ treatment groups significantly inhibited serum concentrations of CRH,ACTH and CORT in NIC withdrawal rats(P<0.01).N/OFQ administration also significantly reduced the levels of inflammatory cytokines TNF-α,IL-1β,and IL-6 in the serum,as well as expression levels of TNF-α,IL-1β and IL-6 mRNA in the CeA(P<0.05 or P<0.01).The treatment with N/OFQ at both doses significantly alleviated neuronal damage in the CA1 region of the hippocampus and markedly re-duced thelevels of NE and TH protein expression in the CeA of NIC withdrawal rats(P<0.01).CONCLUSION:N/OFQ alleviates anxiety-like behavior in NIC withdrawal rats through mechanisms related to the regulation of HPA axis hormone levels and inflammatory factors.
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