Purpose:
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 μ3 opioid receptors.
Methods:
New Zealand rabbits were used in this study. They were pretreated with the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME, 1%, 30 μL), 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 μg/30 μL) 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 μg/30 μL), or the μ3 opioid receptor inhibitor, l-glutathione (GSH, 1%, 30 μL), 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 μ3 receptors contribute to morphine-induced ocular hypotension and that the reduction of IOP elicited by morphine can be augmented by exogenous NO and CO.
