The delta-opioid receptor agonist (+)BW373U86 regulates BDNF mRNA expression in rats.
delta-Opioid receptor agonists have antidepressant-like effects in behavioral models of depression. Chronic administration of classical antidepressants upregulates mRNA expression of brain-derived neurotrophic factor (BDNF) and its high-affinity tyrosine kinase receptor, TrkB in the frontal cortex and hippocampus of rats. Increases in BDNF and TrkB levels are thought to be important for the therapeutic effects of these drugs. Therefore, we examined the ability of the delta-opioid receptor agonist (+)BW373U86 to regulate BDNF and TrkB mRNA expression in frontal cortex, hippocampus, as well as, basolateral amygdala, endopiriform nucleus, and primary olfactory cortex. At 3 h after a single administration of (+)BW373U86 animals were killed and BDNF and TrkB mRNA levels were examined by in situ hybridization. BDNF mRNA levels produced by (+)BW373U86 were compared to acute administration of the antidepressants desipramine and bupropion. A behaviorally antidepressant dose of 10 mg/kg (+)BW373U86 increased BDNF mRNA expression in all regions examined; a smaller dose of (+)BW373U86 (1 mg/kg) significantly increased BDNF mRNA expression only in frontal cortex. The delta-opioid receptor antagonist naltrindole blocked (+)BW373U86-mediated increases in BDNF mRNA expression. In addition, tolerance developed to increased BDNF mRNA expression with repeated injection, except in frontal cortex. Midazolam was administered to some animals to prevent the convulsions produced by (+)BW373U86, but midazolam did not block delta-opioid receptor-mediated increases in BDNF mRNA expression in frontal cortex, hippocampus, or amygdala. Unlike desipramine and bupropion, (+)BW373U86 upregulated BDNF mRNA expression acutely (within 3 h after a single administration). These data support the concept that delta-opioid receptor agonists may have antidepressant potential, and could be good targets for the development of faster-acting antidepressants.
Torregrossa
Mary M
MM
Neuroscience Doctoral Program, University of Michigan, Ann Arbor, MI, USA.
Isgor
Ceylan
C
Folk
John E
JE
Rice
Kenner C
KC
Watson
Stanley J
SJ
Woods
James H
JH
D000704:Analysis of Variance; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D000928:Antidepressive Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D016642:Bupropion / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004361:Drug Tolerance; D005786:Gene Expression Regulation / Q000187:drug effects*; D007103:Immobilization; D017403:In Situ Hybridization / Q000379:methods; D008297:Male; D008874:Midazolam / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000819:agonists*; D013550:Swimming; D013997:Time Factors; D015854:Up-Regulation
D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D001549:Benzamides; D019208:Brain-Derived Neurotrophic Factor; D009292:Narcotic Antagonists; D010879:Piperazines; D012333:RNA, Messenger; D017465:Receptors, Opioid, delta; D016642:Bupropion; C083877:BW 373U86; D009271:Naltrexone; D020813:Receptor, trkB; C055382:naltrindole; D008874:Midazolam; D003891:Desipramine