The nociceptin/orphan FQ system plays a role in the locus coeruleus of buprenorphine-induced withdrawal

[Speaker] Yao-Chang Chiang:1,2
[Co-author] Junyi Wu:1,3, Dong Chuang Wu:3
1:Center for Drug Abuse and Addiction, China Medical University Hospital, China Medical University, Taiwan, 2:Department of Nursing, Division of Basic Medical Sciences, Chang Gung Institute of Technology, Taiwan, 3:Graduate Institute of Biomedical Sciences, China Medical University, Taiwan

Opioid withdrawal is accompanied with a series of physiological and mental disturbances that hinder the abusers back normal life. Understanding the mechanisms involved in withdrawal symptoms could help opioid addicts. Buprenorphine, a maintenance agent, that has benefits on less addictive liability and respiratory depression than methadone. Buprenorphine is acting on both μ-opioid receptor (MOR) and nociceptin receptor (NOPR) at high doses (detoxification doses). The locus coeruleus (LC) region, presented abundant MOR, NOPR and GABAARs, increases of LC neurons activities are directly linked to the withdrawal symptoms. Furthermore, LC express unique subunits (ε and θ) of GABAARs. However, what is the role of NOPR and GABAARs in withdrawal formation remains less studied.
The male Sprague-Dawley rats age 8-12 weeks were received vehicle, or buprenorphine (0.1, 1, 3 mg/kg) for 5 days. Precipitated withdrawal behavioral signs were observed and counted for 30 min followed NOPR antagonist J113,397 (4 mg/kg) or non-selected opioid receptor antagonist naloxone (10 mg/kg) administration after 24 h of the subject received the last vehicle or buprenorphine treatment. Buprenorphine receiving animals were sacrificed and isolated LC for real-time RT-PCR (mRNA changes of target genes) and immunoblotting (changes of candidate proteins) analyses. The special type of GABAAR has also been transfer to HEK cell for electrophysiological assay.
Our preliminary results showed that higher frequencies of withdrawal signs were precipitated by systemic injection of J113,397, with a dose dependent manner for buprenorphine. Pretreatment with Naloxone did not full block J113,397 precipitate buprenorphine-induced withdrawal. For investigating the underlying cellular mechanisms of LC, immunohistochemistry was used to identify the NOPR signals and the LC location for further tissues isolation. Results also showed that buprenorphine treatments increased the expressions of NOPR mRNA and protein, also observed on nociceptin (NOP). In addition, the beta-arrestin and protein kinase C have been reported that associated to the opioid receptors internalization, that were also changed in our current study.
The study reveals that cellular nociceptin/orphan FQ system changes in the LC might affects the buprenorphine-induced withdrawal
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