DOPA and 5-HTP accumulated in vivo in rat brain after decarboxylase inhibition with NSD 1015 (3-hydroxybenzylhydrazine). This accumulation was linear for the first 30 min and occurred in several brain regions over a wide range of NSD 1015 doses. After a peripheral decarboxylase inhibitor much less, if any, DOPA or 5-HTP accumulated in the brain. The accumulation of DOPA was prevented by H 44/68 (methylester of α-methyl para-tyrosine), a tyrosine hydroxylase inhibitor. DOPA, which accumulated before H 44/68 was given, appeared stable for at least 20 min. There were no significant changes in the levels of NA, DA, 5-HT or tryptophan shortly after NSD 1015 administration, but a rise in tyrosine was noted. Increased brain tyrosine after l-tyrosine administration did not alter the DOPA accumulation, however. These data as well as the distribution of the accumulated amino acids suggest that the accumulation of DOPA and 5-HTP after decarboxylase inhibition occurs intraneuronally, that the decarboxylase enzyme is completely inhibited, and that the accumulated products are not appreciably metabolized or transported from the region studied. Amine synthesis rates and rate constants were calculated from the data and compare well with similar values determined by other methods. Thus this accumulation appears to be a reliable measure of the in vivo hydroxylation of tyrosine and tryptophan.

Simultaneous measurement of tyrosine and tryptophan hydroxylase activities in brain in vivo using an inhibitor of the aromatic amino acid decarboxylase.

Opioid treatment of pain is generally safe with 0.5% or less events from respiratory depression. However, fatalities are regularly reported. The only treatment currently available to reverse opioid respiratory depression is by naloxone infusion. The efficacy of naloxone depends on its own pharmacological characteristics and on those (including receptor kinetics) of the opioid that needs reversal. Short elimination of naloxone and biophase equilibration half-lives and rapid receptor kinetics complicates reversal of high-affinity opioids. An opioid with high receptor affinity will require greater naloxone concentrations and/or a continuous infusion before reversal sets in compared with an opioid with lower receptor affinity. The clinical approach to severe opioid-induced respiratory depression is to titrate naloxone to effect and continue treatment by continuous infusion until chances for renarcotization have diminished. New approaches to prevent opioid respiratory depression without affecting analgesia have led to the experimental application of serotinine agonists, ampakines, and the antibiotic minocycline.

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Incidence, Reversal, and Prevention of Opioid-induced Respiratory Depression.

Regional distribution of monoamines in the cerebral cortex and subcortical structures of the rhesus monkey: concentrations and in vivo synthesis rates.

Enhancement of naloxone penetration through human skin in vitro using fatty acids, fatty alcohols, surfactants, sulfoxides and amides

Background:A naloxone infusion is effective in reducing epidural and intrathecal opioid-related side effects. The use of naloxone infusion concomitant with intravenous morphine patient-controlled analgesia (PCA) has not been evaluated, probably because of an expected direct antagonism of the systemi

Opioid-sparing Effects of a Low-dose Infusion of Naloxone in Patient-administered Morphine Sulfate

Using a specific and sensitive radioimmunoassay, naloxone concentrations in the brains and sera of rats were measured at intervals for four hours following iv injection (5 mg/kg). Decrement curves of naloxone were compared with those after iv injection of morphine (5 mg/kg). Serum concentration of naloxone at 5 minutes was 1.45 +/- 0.1 mug/ml (mean +/- SE) and that of morphine was 1.0 +/- 0.08 mug/ml. Their serum half-lives from one to four hours were approximately the same, 30-40 minutes. With naloxone, the brain-serum concentration ratios ranged from 2.7 to 4.6. Concentration of naloxone in the brain declined parallel to that in the serum. However, with morphine the initial brain concentration was approximately one tenth that in the serum (0.096 +/- 0.04 mug/ml). The brain morphine concentration was sustained for one hour, while serum morphine concentrations declined from 1.0 to 0.19 mug/ml during this period. Two minutes after iv injection of naloxone HCl (0.4 mg) in nine healthy volunteers, the serum drug concentration was 0.01 +/- .001 mug/ml. At 5 minutes, 97 per cent of the administered dose was no longer found in the serum, the serum concentration being 0.004 +/- .0003 mug/ml. From 20 minutes to two hours after injection, the calculated mean serum half-life of naloxone was 64 minutes. These results suggest that the rapid penetrance of naloxone into the brain and the high brain-serum concentration ratio contribute to its rapid onset of action and potency as a narcotic antagonist. The rapid decline of naloxone concentration in the brain found in the animal model, in contrast to that of morphine, could be the basis for its relatively short duration of action.

Pharmacokinetics of naloxone in rats and in man: basis for its potency and short duration of action.

Turnover rates of serotonin and norepinephrine in brain of normal and pargyline-treated rats

When tyrosine-14C is infused intravenously at a constant rate into unanesthetized rats, the specific activity of plasma tyrosine increases curvilinearly with time, producing a concomitant increase in the specific activity of tissue catecholamines. By applying steady-state kinetics to this relationship, a simple model was developed from which the fractional rate constant ( k ) of a catecholamine compartment could be calculated. Catecholamine synthesis rates are obtained by multiplying k by the steady-state amine level. Rates calculated by this method are in good agreement with those calculated from the decline of catecholamine levels after blockade of their synthesis with α-methyltyrosine. By using the present method, it was found that adrenal demedullation results in about a 4-fold increase in the rate of synthesis of heart norepinephrine while brain catecholamine synthesis remains unchanged. It is suggested that catecholamines released from the adrenal medulla may modulate the synthesis of norepinephrine in cardiac sympathetic neurons.

ACKNOWLEDGMENT The skillful assistance of Miss Sonja Lofstrandh is greatly appreciated.

Calculation of the rate of catecholamine synthesis from the rate of conversion of tyrosine-14C to catecholamines. Effect of adrenal demedullation on synthesis rates.

S. H. Ngai

Papers

Pharmacokinetics of naloxone in rats and in man: basis for its potency and short duration of action.

Turnover rates of serotonin and norepinephrine in brain of normal and pargyline-treated rats

Calculation of the rate of catecholamine synthesis from the rate of conversion of tyrosine-14C to catecholamines. Effect of adrenal demedullation on synthesis rates.

Turnover rate measurements of brain serotonin in unanesthetized rats.

Dopamine-β-hydroxylase in dog lymph - effect effect of sympathetic activation