Differential down- and up-regulation of rat brain opioid receptor types and subtypes by buprenorphine.
The induction of opioid receptor adaptation by mixed agonist-antagonists such as buprenorphine has not been investigated. To this end, neonatal rats were given injections of buprenorphine (0.1-2.5 mg/kg/day) and mu binding (Kd and Bmax) to brain membranes was measured with [3H][D-Ala2,MePhe4,Gly-ol5]enkephalin. At doses of buprenorphine of > or = 0.5 mg/kg, mu sites were reduced 47-75%, without changes in affinity. Chronic administration of the structurally related partial agonist diprenorphine (2.5-75 mg/kg) failed to alter mu binding. Apparent loss of sites due to receptor blockade by residual buprenorphine was ruled out by several lines of evidence. Bmax values for delta ([3H][D-Ser2,L-Leu5]enkephalyl-Thr) and kappa ([3H]U69593) binding were elevated 1.9-4.2-fold by buprenorphine treatment. In adult rats buprenorphine (0.5-2.5 mg/kg) reduced mu-opioid binding to forebrain membranes dose dependently, by 25-77%. [3H][D-Ser2,L-Leu5] Enkephalyl-Thr-labeled delta subtype receptors and kappa sites in adult forebrain membranes were up-regulated 2-3-fold. The delta subtype receptors that bind [3H][D-Pen2,D-Pen5]enkephalin in neonatal or adult brain membranes were unaffected by 0.5-2.5 mg/kg buprenorphine treatment. Down-regulation (70-74%) of mu sites and up-regulation (1.9-6.7 fold) of delta and kappa receptors were also observed in synaptic plasma membrane-enriched and microsomal fractions from buprenorphine-treated adult rat brain. Because agonist-induced opioid receptor down-regulation is difficult to elicit in adult mammalian brain, these data indicate that buprenorphine is a useful tool to study brain opioid receptor adaptation in vivo.
Belcheva
M M
MM
E. A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, Missouri 63104.
Barg
J
J
McHale
R J
RJ
Dawn
S
S
Ho
M T
MT
Ignatova
E
E
Coscia
C J
CJ
D000375:Aging / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002047:Buprenorphine / Q000494:pharmacology*; D015536:Down-Regulation; D066298:In Vitro Techniques; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000187:drug effects*; D013347:Subcellular Fractions / Q000378:metabolism; D015854:Up-Regulation
D011957:Receptors, Opioid; D002047:Buprenorphine