Modulation of Ocular Hydrodynamics and Iris Function by Bremazocine, a Kappa Opioid Receptor Agonist

Russell, Karen; Wang, Duan Ran; Potter, David E.

doi:10.1006/exer.2000.0832

Cited by 25 publications

(24 citation statements)

References 29 publications

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“…However, the concentration of cAMP in cells is determined ultimately by the relative rates of activity of the synthetic isozymes of adenylate cyclase and the degradative isozymes of PDE. Because it has been established in our laboratory that -opioid agonists suppress aqueous flow rate and intraocular pressure, in part, by decreasing levels of cAMP in the ICB (Russell et al, 2000;Moore and Potter, 2001), the purpose of this study was to determine the roles of PKC and PDE in -opioid agonist-induced reductions in cAMP levels.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies in our laboratory have demonstrated the ability of -opioid agonists to lower intraocular pressure in rabbits (Russell et al, 2000) as well as reduce levels of cAMP in isolated iris-ciliary bodies (Moore and Potter, 2001). However, the signal transduction events associated with agonist-induced ocular hypotension have not been delineated.…”

Section: Pdbu (10mentioning

confidence: 99%

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Inhibition of cAMP Accumulation by κ-Receptor Activation in Isolated Iris-Ciliary Bodies: Role of Phosphodiesterase and Protein Kinase C

Dortch-Carnes¹,

Potter²

2002

J Pharmacol Exp Ther

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The present study was designed to examine the roles of protein kinase C (PKC) and phosphodiesterase (PDE) in modulating the action of receptor stimulation on cAMP accumulation in isolated iris-ciliary bodies (ICBs) of New Zealand White rabbits. The receptor agonist, (Ϯ)-1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl)methylpiperidine (BRL-52537) (BRL), and the PKC activator, phorbol 12,13-dibutyrate (PDBu), both caused a concentration-dependent inhibition of forskolin-stimulated cAMP production. The inhibitory effect of BRL on cAMP levels was significantly reduced in the presence of the selective receptor antagonist, norbinaltorphimine (10 Ϫ6 M), but the effect of PDBu was not, thus supporting the involvement of -opioid receptors in the response to BRL. In the presence of 3-isobutyl-1-methylxanthine or rolipram (10 Ϫ5 M), the inhibitory effect of BRL or PDBu (10 Ϫ6 M) on cyclic AMP accumulation was abolished. In the presence of the selective PKC antagonist, chelerythrine (10 Ϫ6 M), the inhibitory effect of PDBu or BRL (10 Ϫ6 M) was significantly reduced. Direct measurement of PDE activity demonstrated the ability of BRL and PDBu (10 Ϫ6 M) to augment the activity of these enzymes. Preincubation of ICBs with rolipram (10 Ϫ5 M) or chelerythrine (10 Ϫ6 M) caused significant reversal of both BRL-and PDBu-induced increases in PDE activity. These results indicate that stimulation of PKC and PDE4 activity is part of the complex mechanism whereby -opioid receptor agonists reduce levels of cAMP in the rabbit ICB. This mechanism of action could contribute to the ability of -opioid agonists to suppress aqueous flow rate and to lower intraocular pressure.

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Section: Discussionmentioning

confidence: 99%

Section: Pdbu (10mentioning

confidence: 99%

Inhibition of cAMP Accumulation by κ-Receptor Activation in Isolated Iris-Ciliary Bodies: Role of Phosphodiesterase and Protein Kinase C

Dortch-Carnes¹,

Potter²

2002

J Pharmacol Exp Ther

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“…In control (vehicle-treated) animals, the vehicle (saline) was applied topically to both eyes, and the sampling schedule was the same as those of the treatment group. The topical pretreatment with antagonists norbinaltorphimine (norBNI, 100 g/25 l; Tocris Cookson Inc., Ballwin, MO) or chelerythrine chloride (10 g/25 l; Sigma-Aldrich), a PKC inhibitor, preceded the challenge with BRE by 0.5 h. The topical doses of antagonists were determined from previous experimentation in rabbits (Russell et al, 2000) or were extrapolated from previously published in vivo doses in rabbits (Sandhu et al, 1997) and monkeys (Tian et al, 2000).…”

Section: Methodsmentioning

confidence: 99%

Bremazocine Increases C-Type Natriuretic Peptide Levels in Aqueous Humor and Enhances Outflow Facility

Potter¹,

Russell²,

Manhiani³

2004

J Pharmacol Exp Ther

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A relatively selective agonist of opioid receptors (KOR), bremazocine (BRE), lowers intraocular pressure in rabbits, in part, by increasing natriuretic peptide levels in aqueous humor and by enhancing total outflow facility (TOF). Natriuretic peptide (NP) levels [atrial NP (ANP), brain NP (BNP), and C-type NP (CNP)] were measured in aqueous humor of rabbits either by radioimmunoassay or enzyme immunoassay. TOF was determined in rabbits by two-level constant pressure perfusion of the anterior chamber. Experimental regimens included topical treatment with BRE in the presence or absence of KOR antagonist (norbinaltorphimine), protein kinase C inhibitor (chelerythrine), and natriuretic peptide receptor antagonist (isatin). The rank order of basal NP levels in aqueous humor of rabbits was BNP & CNP Ͼ ANP. Topical administration of BRE (1-100 g) caused dose-related elevations of CNP levels in aqueous humor that were inhibited by topical pretreatment with either norbinaltorphimine (100 g, bilaterally) or chelerythrine (10 g, bilaterally). Topically administered BRE (100 g) also elevated levels of ANP and BNP in aqueous humor and evoked an 80% increase in TOF. The increase in TOF was antagonized by topical pretreatment with either norbinaltorphimine (100 g, bilaterally) or isatin (100 g, bilaterally). Bremazocine induced an increase in NP (ANP, BNP, and CNP) levels and TOF in rabbits by activating KOR. The increase in CNP levels elicited by BRE was inhibited by norbinaltorphimine and chelerythrine; therefore, this event is most likely mediated by a KOR-linked activation of protein kinase C. These data provide evidence that the increase in TOF elicited by BRE was mediated by a KORactivated paracrine effect of NPs on tissues within ocular outflow tract(s).Neuroendocrine regulation of fluid homeostasis throughout the body depends, in part, on the activity of the natriuretic peptide system. Of the three natriuretic peptides [i.e., atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP)], the sequences of ANP and CNP are more highly conserved among the species, whereas the structure of BNP varies greatly. It has been proposed that natriuretic peptides generated within the eye contribute to the regulation of aqueous humor dynamics; however, the understanding of how this ocular neuroendocrine system is modulated is very limited.Recently, molecular evidence has been presented for neuroendocrine functions in the ciliary epithelium Ortego and Coca-Prados, 1999). Moreover, it has been postulated that natriuretic peptides released by drugs from ciliary epithelial cells could then act in an autocrine and/or paracrine manner to change intraocular pressure (IOP). Recent reports have shown that ocular hypotensive drugs such as opioid receptor (KOR) agonists (bremazocine) (Russell et al., 2001;Russell and Potter, 2002) and imidazoline-1/␣2 agonists (Ogidigben et al., 1999(Ogidigben et al., , 2002 elevate ANP levels in aqueous humor of rabbits.The current study was conducted to: 1) ...

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“…In this study, the iris-ciliary body was used for two reasons: (1) previously, BRE was shown to inhibit aqueous humor formation in rabbits [5]; (2) the presumed site of ANP production and release is in the ciliary epithelium [10].…”

Section: Preparation Of Iris-ciliary Bodiesmentioning

confidence: 99%

“…Recent studies in our laboratory have shown that the kappa-opioid receptor agonists, bremazocine (BRE) and spiradoline, reduce intraocular pressure (IOP) in rabbits [4,5]. Moreover, BRE has been demonstrated to increase levels of atrial natriuretic peptide (ANP) in the aqueous humor of rabbits [6].…”

Section: Introductionmentioning

confidence: 99%

Effect of Bremazocine, a Kappa-Opioid Receptor Agonist, on Inositol Phosphate Formation in Isolated Iris-Ciliary Bodies

Dortch-Carnes

Potter²

2002

Pharmacology

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The goal of the current study was to examine the effect of the kappa-opioid agonist, bremazocine (BRE), on inositol phosphate (IP) formation in the rabbit iris-ciliary body (ICB). Concentrations of BRE (10^–7 to 10^–5M) augmented levels of IP. Incubation of ICBs with BRE (10^–6M) produced a time-dependent increase in IP levels that peaked at 60 s and declined to basal levels by 5 min. The increase in IP levels produced by BRE (10^–6M) was inhibited by the kappa-opioid receptor antagonist, nor-binaltorphimine (nor-BNI, 10^–7 to 10^–5M) and by activation of PKC with PDBu (10^–7M). These results demonstrate that kappa-opioid receptor activation by BRE in the rabbit ICB is linked to IP production. Thus, opioid agonist-induced increases in IP activity could play a role in BRE-induced increases in atrial natriuretic peptide release and alterations in aqueous humor dynamics.

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Modulation of Ocular Hydrodynamics and Iris Function by Bremazocine, a Kappa Opioid Receptor Agonist

Cited by 25 publications

References 29 publications

Inhibition of cAMP Accumulation by κ-Receptor Activation in Isolated Iris-Ciliary Bodies: Role of Phosphodiesterase and Protein Kinase C

Inhibition of cAMP Accumulation by κ-Receptor Activation in Isolated Iris-Ciliary Bodies: Role of Phosphodiesterase and Protein Kinase C

Bremazocine Increases C-Type Natriuretic Peptide Levels in Aqueous Humor and Enhances Outflow Facility

Effect of Bremazocine, a Kappa-Opioid Receptor Agonist, on Inositol Phosphate Formation in Isolated Iris-Ciliary Bodies

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