The stereoisomer (+)-naloxone potentiates G-protein coupling and feeding associated with stimulation of mu opioid receptors in the parabrachial nucleus.
Classically, opioids produce their effects by activating Gi-proteins that inhibit adenylate cyclase activity. Previous studies proposed that mu-opioid receptors can also stimulate adenylate cyclase due to an initial transient coupling to Gs-proteins. Treatment with ultra-low doses of the nonselective opioid antagonist (-)-naloxone or its inactive enantiomer (+)-naloxone blocks this excitatory effect and enhances Gi-coupling. Previously we reported that infusion of the mu-opioid receptor agonist [D-Ala2, N-Me-Phe4, Glycinol5]-Enkephalin (DAMGO) into the mu-opioid receptor expressing lateral parabrachial nucleus increases feeding. Pretreatment with (-)-naloxone blocks this effect. We used this parabrachial circuit as a model to assess cellular actions of ultra-low doses of (-)-naloxone and (+)-naloxone in modifying the effects of DAMGO. Our results showed that an ultra-low concentration of (-)-naloxone (0.001 nM) and several concentrations of (+)-naloxone (0.01-10 nM) enhanced DAMGO-stimulated guanosine-5'-0-(γ-thio)-triphosphate incorporation in parabrachial sections in vitro. Further, we analyzed the relevance of these effects in vivo. In the present study, we show that (+)-naloxone can potentiate DAMGO-induced feeding at doses at which (-)-naloxone was an antagonist. These results implicated (+)-naloxone as a novel tool for studying mu-opioid receptor functions and suggest that (+)-naloxone may have therapeutic value to enhance clinical actions of opiate drugs.
Drexel University College of Medicine, Department of Pharmacology and Physiology, Philadelphia, PA 19102, USA.
Nayla N
NN
Chaijale
Vincent J
VJ
Aloyo
Kenny J
KJ
Simansky
D000701:Analgesics, Opioid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004357:Drug Synergism; D004435:Eating / Q000187:drug effects; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000819:agonists* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009270:Naloxone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009994:Osmolar Concentration; D011149:Pons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013237:Stereoisomerism
D000701:Analgesics, Opioid; C522851:Gnai1 protein, rat; D009292:Narcotic Antagonists; D009419:Nerve Tissue Proteins; C485765:Oprm1 protein, rat; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009270:Naloxone; D019206:GTP-Binding Protein alpha Subunits, Gi-Go