Abstract
κ-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 κ-opioid receptor agonist and antagonist, respectively, along with pertussis toxin (PTX), were used to evaluate the effect of 1) κ-opioid receptors on [3H]norepinephrine (NE) release from postganglionic sympathetic neurons, and 2) cAMP accumulation. BRE caused dose-related (0.1, 1, and 10 μM) inhibition of electrically stimulated [3H]NE release from ICBs to 77, 57, and 36% of the control, respectively. Nor-BNI antagonized the inhibition of [3H]NE release by BRE, while PTX pretreatment limited the suppressive effect of BRE (1 and 10 μM). When used alone, BRE (0.01, 0.1, 1, and 10 μM) 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 μM) 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 κ-opioid receptors involved in some of the ocular actions of BRE are linked to a Gi/o protein.
Footnotes
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This study was supported by Grant EY11977 from the National Eye Institute. This work was previously presented at The Association for Research in Vision and Ophthalmology, March, 2000; Invest Ophthalmol Visual Sci41:S251.
- Abbreviations:
- PTX
- pertussis toxin
- BRE
- bremazocine
- NE
- norepinephrine
- nor-BNI
- norbinaltorphimine
- ICB
- iris-ciliary body
- ISO
- isoproterenol
- Received March 15, 2001.
- Accepted May 17, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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