Quantitative autoradiography of adenosine receptors and NBTI-sensitive adenosine transporters in the brains of mice deficient in the preproenkephalin gene.
There is a large body of evidence indicating important interactions between the adenosine and the opioid systems in regulating pain, opioid dependence and withdrawal. Mice lacking the proenkephalin gene and therefore lacking the endogenous enkephalin peptides have been successfully developed and exhibit decreased locomotor activity, are hyperalgesic and show enhanced anxiety and aggression. In addition, an upregulation of mu and delta receptors was also observed in the brains of knockout mice. To investigate if there are any compensatory alterations in adenosine systems in the brains of mutant mice, we have carried out quantitative autoradiographic mapping of A(1) and A(2A) adenosine receptors and nitrobenzylthioinosine (NBTI)-sensitive adenosine transporters in the brains of wild-type and homozygous enkephalin knockout mice. Adjacent coronal brain sections were cut from brains of +/+ and -/- mice for the determination of binding of [(3)H]1,3-dipropyl-8-cyclopentylxanthine ([(3)H]DPCPX), [(3)H]2-[p-(2-carbonylethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosine ([(3)H]CGS21680) or [(3)H]NBTI to A(1) and A(2A) adenosine receptors and NBTI-sensitive adenosine transporters, respectively. A small but significant increase in [(3)H]DPCPX and [(3)H]NBTI binding but no significant change in [(3)H]CGS21680 binding was detected in enkephalin knockout brains. The results provide further evidence of functional interactions in the brain between opioid receptors and A(1) adenosine receptors as well as NBTI-sensitive adenosine transporters but not A(2A) receptors.
Pharmacology Group, School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey GU2 7XH, United Kingdom.
Alexis
A
Bailey
Daniel
D
Weber
A
A
Zimmer
A M
AM
Zimmer
Susanna M O
SM
Hourani
Ian
I
Kitchen
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004745:Enkephalins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D033703:Nucleoside Transport Proteins; D011485:Protein Binding; D011498:Protein Precursors / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism*; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014970:Xanthines / Q000378:metabolism
D004745:Enkephalins; D026901:Membrane Transport Proteins; D033703:Nucleoside Transport Proteins; D011498:Protein Precursors; D018047:Receptors, Purinergic P1; D014970:Xanthines; C444719:adenosine transporter; D013868:Thioinosine; C033660:preproenkephalin; C051360:1,3-dipropyl-8-cyclopentylxanthine; C001789:4-nitrobenzylthioinosine