Morphine administration modulates expression of Argonaute 2 and dopamine‐related transcription factors involved in midbrain dopaminergic neurons function

• Published in: British journal of pharmacology Vol. 168; no. 8; pp. 1889 - 1901
• Main Authors: García‐Pérez, D, Sáez‐Belmonte, F, Laorden, ML, Núñez, C, Milanés, MV
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-04-2013
• Subjects: 3,4-Dihydroxyphenylacetic Acid - metabolism; Ago2; Animals; Argonaute Proteins - genetics; Argonaute Proteins - metabolism; Body Weight - drug effects; DA turnover; Dopamine; Dopamine - metabolism; Drug Implants; Gene Expression Regulation - drug effects; Homeodomain Proteins - metabolism; Injections, Intraperitoneal; Male; Mesencephalon - drug effects; Morphine - administration & dosage; Naloxone - administration & dosage; Neurons; Nuclear Receptor Subfamily 4, Group A, Member 2 - metabolism; Nucleus Accumbens - metabolism; Nurr1; opiate dependence; Phosphorylation; Pitx3; Rats; Rats, Wistar; Research Papers; Rodents; Substance-Related Disorders - metabolism; Substance-Related Disorders - pathology; Transcription factors; Transcription Factors - metabolism; Tyrosine 3-Monooxygenase - metabolism; Ventral Tegmental Area - metabolism
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.12083

Background and Purpose
Alterations in transcription factors that regulate the development and maintenance of dopamine (DA) neurons (such as Nurr1 and Pitx3) play an important role in the pathogenesis of addiction diseases. We have examined the effects of acute and chronic morphine and morphine withdrawal on TH expression and activity as well as expression of Nurr1, Pitx3 and Ago2 in the ventral tegmental area (VTA) and nucleus accumbens (NAc) of the rat.
Experimental Approach
Rats were injected acutely with morphine and decapitated 1 or 2 h later. Another set of rats were made dependent on morphine by implantation of two morphine pellets. Precipitated withdrawal was induced by injection of naloxone. Ago2, Pitx3, Nurr1, total TH (tTH), TH phosphorylated at Ser31 and at Ser40, and 3,4‐Dihydroxyphenylacetic acid, and DA determination in the VTA and/or NAc were measured using immunoblotting, HPLC and immunofluorescence.
Key Results
Acute morphine produced a marked increase in TH activity and DA turnover in the NAc, concomitantly with increased Nurr1 and Pitx3 expression in the VTA. In contrast, precipitated morphine withdrawal decreased TH activation, TH expression and did not increase DA turnover in the NAc. These effects paralleled decreases in Ago2 expression, which was accompanied by increased Nurr1 and Pitx3, TH activity and normalized TH protein levels in the VTA.
Conclusions and Implications
The combined decrease in Ago2 and increases in Nurr1 and Pitx3 might represent some of the mechanisms that served to protect against accumbal TH regulation observed in morphine withdrawn rats, which may be critical for DA bioavailability to influence behaviour.