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.
Department of Experimental and Clinical Pharmacology, School of Medicine, University of Catania, Catania, Italy.
Edoardo
E
Stagni
Claudio
C
Bucolo
Roberto
R
Motterlini
Filippo
F
Drago
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