Morphine-induced ocular hypotension is modulated by nitric oxide and carbon monoxide: role of mu3 receptors.
OBJECTIVE
Recent findings generated from our laboratory have demonstrated the involvement of nitric oxide (NO) in morphine-induced reduction of intraocular pressure (IOP). The present study was designed to investigate the possible involvement of carbon monoxide (CO) in morphine-induced reduction of IOP and the role of mu(3) opioid receptors.


METHODS
New Zealand rabbits were used in this study. They were pretreated with the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME, 1%, 30 microL), or an inhibitor of heme oxygenase (HO), zinc protoporphyrin-IX (ZnPP-IX; 0.1 mg/kg; i.v.). The same animals were then treated with morphine (100 microg/30 microL) with or without NO or CO donors administration, sodium nitroprusside (SNP) and tricarbonylchloro(glycinato)ruthenium(II) (CORM-3), respectively. A separate set of animals were pretreated with the nonselective opioid receptor antagonist, naloxone (100 microg/30 microL), or the micro(3) opioid receptor inhibitor, L-glutathione (GSH, 1%, 30 microL), in the presence of SNP or CORM-3 followed by morphine administration. IOP measurements were taken at different times after monolateral instillation of morphine.


RESULTS
Morphine induced a significant decrease in IOP and pretreatment with ZnPP-IX or L-NAME significantly prevented this effect whereas administration of NO or CO donors amplified morphine-induced decrease in IOP. This effect was partially abrogated both by pretreatment with ZnPP-IX or L-NAME, and by pretreatment with naloxone and GSH suggesting that the decrease in IOP relies on exogenous NO and CO liberated from SNP and CORM-3, respectively.


CONCLUSIONS
We conclude that the endogenous NO/CO system and micro(3) receptors contribute to morphine-induced ocular hypotension and that the reduction of IOP elicited by morphine can be augmented by exogenous NO and CO.
Stagni
Edoardo
E
Department of Experimental and Clinical Pharmacology, School of Medicine, University of Catania, Catania, Italy.
Bucolo
Claudio
C
Motterlini
Roberto
R
Drago
Filippo
F
D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism* / Q000494:pharmacology; D004791:Enzyme Inhibitors; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors; D007429:Intraocular Pressure / Q000187:drug effects; D009020:Morphine / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D015814:Ocular Hypotension / Q000139:chemically induced* / Q000503:physiopathology; D020033:Protein Isoforms / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D011817:Rabbits; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D011524:Protoporphyrins; D017450:Receptors, Opioid, mu; C017803:zinc protoporphyrin; D009569:Nitric Oxide; D009020:Morphine; D002248:Carbon Monoxide; D019001:Nitric Oxide Synthase; D006419:Heme Oxygenase (Decyclizing); D019331:NG-Nitroarginine Methyl Ester