Differential down- and up-regulation of rat brain opioid receptor types and subtypes by buprenorphine
Belcheva, M.M.; Barg, J.; McHale, R.J.; Dawn, S.; Ho, M.T.; Ignatova, E.; Coscia, C.J.
Molecular Pharmacology 44(1): 173-179
1993
ISSN/ISBN: 0026-895X PMID: 8393519 Document Number: 414915
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 (K-d and B-max) to brain membranes was measured with (3H)(D-Ala-2,MePhe-4,Gly-ol-5)enkephalin. At doses of buprenorphine of gtoreq 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 A binding. Apparent loss of sites due to receptor blockade by residual buprenorphine was ruled out by several lines of evidence. B-max values for delta ((3H)(D-Ser-2,L-Leu-5)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 A-opioid binding to forebrain membranes dose dependently, by 25-77%. (3H)(D-Ser-2,L-Leu-5) Enkephalyl-Thr-labeled delta subtype receptors and KAPPA sites in adult forebrain membranes were up-regulated 2-3-fold. The 6 subtype receptors that bind (3H)(D-Pen-2,D-Pen-5)enkephalin in neonatal or adult brain membranes were unaffected by 0.5-2.5 mg/kg buprenorphine treatment. Down-regulation (70-74%) of u 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.