Biphasic alterations of cAMP levels and inhibition of norepinephrine release in iris-ciliary body by bremazocine.
Kappa-opioid receptor agonists have been shown to reduce intraocular pressure in rabbits and monkeys. This study was designed to investigate mechanisms in the iris-ciliary body (ICB) that may be involved in bremazocine (BRE)-induced ocular hypotension in New Zealand White rabbits. Using ICBs, BRE and norbinaltorphimine (nor-BNI), relatively selective kappa-opioid receptor agonist and antagonist, respectively, along with pertussis toxin (PTX), were used to evaluate the effect of 1) kappa-opioid receptors on [(3)H]norepinephrine (NE) release from postganglionic sympathetic neurons, and 2) cAMP accumulation. BRE caused dose-related (0.1, 1, and 10 microM) inhibition of electrically stimulated [(3)H]NE release from ICBs to 77, 57, and 36% of the control, respectively. Nor-BNI antagonized the inhibition of [(3)H]NE release by BRE, while PTX pretreatment limited the suppressive effect of BRE (1 and 10 microM). When used alone, BRE (0.01, 0.1, 1, and 10 microM) caused stimulation of cAMP levels in ICBs, however, similar concentrations caused inhibition of isoproterenol (ISO)-stimulated cAMP production. Pretreatment of ICBs with nor-BNI (10 microM) or PTX (150 ng/ml) antagonized BRE-induced suppression of ISO-stimulated cAMP. These data demonstrate that BRE acts at multiple [prejunctional (neuronal) and postjunctional] sites in the ICB. BRE had a biphasic effect on ISO-stimulated adenylyl cyclase activity; enhancing cAMP levels at low concentrations and inhibiting cAMP production at high concentrations. Based on the modifications induced by PTX pretreatment, the kappa-opioid receptors involved in some of the ocular actions of BRE are linked to a G(i/o) protein.
Russell
K R
KR
Morehouse School of Medicine, Department of Pharmacology and Toxicology, Atlanta, Georgia 30310-1495, USA. Russellk@msm.edu
Potter
D E
DE
D037361:Adenylate Cyclase Toxin; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001575:Benzomorphans / Q000494:pharmacology*; D002924:Ciliary Body / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D007498:Iris / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009469:Neuromuscular Junction / Q000187:drug effects; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D037342:Pertussis Toxin; D011817:Rabbits; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013564:Sympathetic Nervous System / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D000700:Analgesics; D001575:Benzomorphans; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; D010566:Virulence Factors, Bordetella; C051844:norbinaltorphimine; D009271:Naltrexone; D000242:Cyclic AMP; D037342:Pertussis Toxin; C027248:bremazocine; D009638:Norepinephrine