Catechol-O-methyltransferase: potential relationship to idiopathic hypertension

Catecholamine signaling pathways in the peripheral and central nervous systems (PNS, CNS, respectively) utilize catechol-O-methyltransferase (COMT) as a major regulatory enzyme responsible for deactivation of dopamine (DA), norepinephrine (NE) and epinephrine (E). Accordingly, homeostasis of COMT gene expression is hypothesized to be functionally linked to regulation of autonomic control of normotensive vascular events. Recently, we demonstrated that morphine administration in vitro resulted in decreased cellular concentrations of COMT-encoding mRNA levels, as compared to control values. In contrast, cells treated with E up regulated their COMT gene expression. In sum, these observations indicate a potential reciprocal linkage between end product inhibition of COMT gene expression by E and morphine. Interestingly, the observed effects of administered E on COMT gene expression suggest an enhancement of its own catabolism or, reciprocally, a stimulation morphine biosynthesis

Morphine 6beta glucuronide: fortuitous morphine metabolite or preferred peripheral regulatory opiate?

International audienceMorphine-6beta-glucuronide (M6G), a metabolite of morphine that the brain can produce, is an opiate agonist that appears to have a greater analgesic potency than morphine. M6G has a 1-octanol/water partition coefficient 187 times lower than that of morphine and M6G has a blood brain barrier permeability 57 times lower than morphine. The brain uptake rate however is only 32 times lower, suggesting that an active transport mechanism might be present. Furthermore, evidence for a distinct receptor for M6G also appears to be emerging. Real time polymerase chain reactions allowed for the discovery of single nucleotide polymorphisms (SNP's) in the human mu opioid receptor gene. The most common SNP is a substitution at base118 where A is replaced with G (A118G). This SNP has a decreased potency for M6G in individuals possessing it whereas the potency of morphine is unaffected by this SNP. The possibility that a peripheral opiate signaling system, using M6G and its distinct receptor, exists seems plausible. Taken together, if a distinct M6G signaling mechanism does exist, the fact that morphine can be converted into a more water soluble compound that might be more potent would not be an accident