I. K. Ho

Pharmacological manipulation of gamma-aminobutyric acid (GABA) in morphine analgesia, tolerance and physical dependence

Abstract The findings from our laboratory indicated that pharmacological manipulations of GABA system modified morphine analgesia, tolerance and physical dependence. Elevating brain levels of GABA by slowing its destruction with aminooxyacetic acid not only antagonized the analgesic action of morphine in both non-tolerant and tolerant mice, but also enhanced the development of tolerance and physical dependence. On the other hand, blockade of postsynaptic sites of GABA receptors by bicuculline resulted in an inhibition of tolerance and dependence development. Administration of 2,4-diaminobutyric acid, an inhibitor of GABA uptake in the neurons, antagonized morphine analgesia in both non-tolerant and tolerant mice. However, it did not modify naloxone precipitated withdrawal jumping. On the contrary, β-alanine, an inhibitor of the GABA uptake process in glial cells, potentiated naloxone precipitated withdrawal jumping in morphine dependent mice, but it had no effect on morphine antinociception in both non-tolerant and tolerant mice.

A model for the rapid development of dispositional and functional tolerance to barbiturates

The s.c. implantation of a 75 mg pentobarbital pellet in the back of a conscious mouse resulted in a much more rapid development of tolerance to barbiturates than that produced in mice receiving daily i.p. injections of 75 mg/kg sodium pentobarbital. Acceleration in tolerance development by pentobarbital pellet implantation was evidenced by a decrease in sleeping time after the challenge with either sodium pentobarbital or sodium barbital. The degree of hepatic microsomal drug enzyme induction after pentobarbital pellet implantation also was found to be significantly higher than that produced by the injection technique. Further studies demonstrated that the threshold for pentylenetetrazol-induced seizures was significantly reduced compared to that of the sodium pentobarbital daily injected and control groups. These studies provide an animal model for studying the mechanism of barbiturate tolerance and dependence.

Effect of cyclic nucleotides and phosphodiesterase inhibition on morphine tolerance and physical dependence

Abstract The effects of cyclic nucleotides and theophylline were assessed in mice rendered tolerant to and physically dependent on morphine by the pellet implantation procedure. Tolerance was quantified by the increase in amount of morphine to produce analgesia and dependence by the decrease in amount of naloxone to precipitate withdrawal jumping. By these criteria, pretreatment with a single intravenous injection of cyclic 3′, 5′-adenosine monophosphate (cAMP) was found to enhance markedly tolerance and dependence development. Repeated injections of theophylline were also affective. Cycloheximide and beta-adrenergic blockers prevented the accelerating effect of cAMP and with more frequent administration also decreased the development of tolerance and dependence. It is concluded that cAMP may have a role in morphine tolerance and dependence development.

Influence of 5,6-dihydroxytryptamine on morphine tolerance and physical dependence.

Abstract The intracerebral administration of 5,6-dihydroxytryptamine (5,6-DHT) in the mouse inhibited the development of tolerance to and physical dependence on morphine induced by morphine pellet implantation. Reduction in tolerance development by 5,6-DHT was evidenced by the decreased amount of morphine necessary to produce analgesia and reduction in dependence development by the increase in the amount of naloxone necessary to induce precipitated withdrawal jumping in comparison with morphine-implanted animals receiving saline. Further evidence that 5,6-DHT reduced dependence development on morphine was evidenced by the fact that 5,6-DHT decreased the loss in body weight which occurred after abrupt morphine withdrawal. At the dose of 5,6-DHT used in this study (60 μg of the creatinine sulfate dihydrate 24 hr prior to morphine pellet implantation), the 5-HT level in the brain 4 days later was 75% of that of the control group while catecholamine levels remain unchanged. These studies substantiate the suggestion from this laboratory that central serotonergic system may be associated in the development of morphine tolerance and dependence.

Effect of chronic morphine treatment on brain chromatin template activities in mice

Abstract Chromatins have been isolated from both placebo- and chronic morphine-treated mice. The specific activity of chromatin-directed UTP incorporation was measured. Evidence is presented to show that the chromatin template activity isolated from tolerant animals is increased. The increase may be due to the alteration of non-histone protein in chromatin. This is a narcotic-specific phenomenon, since the morphine-induced increase can be blocked by naloxone.

Enhancement of pentobarbital effect by continuous administration of morphine in the mouse

Abstract These studies demonstrated that continuous morphine treatment from implantation of a 75 mg morphine pellet for 3 days potentiated pentobarbital narcosis and enhanced pentobarbital hypothermia. In the morphine implant mice, sleeping time after two different doses of pentobarbital was greater than 2.5 × the sleeping time in placebo pellet implant animals and also greater than sleeping time in animals treated acutely with morphine prior to pentobarbital. Moreover, in the morphine implant mice both the degree and duration of pentobarbital induced hypothermia were enhanced. The above findings were due to slower rate of metabolism of pentobarbital as evidenced by inhibition of hepatic N-demethylation, and higher levels of brain and serum pentobarbital in the morphine implant mice compared to both placebo and acute morphine mice.

The antagonistic effects of 5-ethyl-5-(3-hydroxy-1-methylbutyl)-barbituric acid on pentobarbital narcosis in both naïve and tolerant mice

Abstract These studies demonstrated that 5-ethyl-5-(3-hydroxyl-1-methyl-butyl)-barbituric acid (PB-OH), a major metabolite of pentobarbital, antagonized pentobarbital-induced narcosis in both naive and pentobarbital tolerant mice. In PB-OH pretreated mice, the sleeping time induced by sodium pentobarbital was significantly shorter than that of the saline control animals. However, PB-OH failed to modify the pentobarbital-induced hypothermia. The findings also demonstrated that hepatic microsomal enzyme activity and half lives of pentobarbital and PB-OH in both plasma and brain were not modified by the pretreatment of PB-OH. The specific antagonistic effect of PB-OH appears to be a direct effect on sites in the CNS.

Acceleration of pentobarbital metabolism in tolerant mice induced by pentobarbital pellet implantation.

Abstract The time course of inductions of N-demethylation and pentobarbital hydroxylation of hepatic drug metabolizing system in continuous pentobarbital administration by pentobarbital pellet implantation in the mouse is presented. The results also demonstrate that hepatic microsomal drug-metabolizing enzymes in the mouse could be induced much faster by a single pentobarbital pellet implantation than by the ordinary parenteral administration technique. The reduction of pentobarbital half-life ( T 1 2 ) in plasma, brain and liver of the animals which had been implanted with a pentobarbital pellet also substantiates the acceleration of pentobarbital metabolism in the mouse by the pellet implantation method. The results show that the T 1 2 of pentobarbital in plasma, brain and liver of pentobarbital pellet implanted groups is only 1 2 , 1 6 and 1 9 of that of the placebo control group, respectively. The studies on urinary excretion of pentobarbital and its metabolites also reveals that pentobarbital pellet implantation induced much faster rate of metabolism of pentobarbital in the mouse.

Effect of pargyline on morphine tolerance and physical dependence development in mice

The effects of single and repeated pargyline administration on morphine antinociception in both naive and morphine-tolerant mice and on naloxone-precipitated withdrawal in morphine tolerant-dependent animals were investigated. Adult, male Swiss-Webster mice were rendered tolerant to and dependent on morphine by the s.c. pellet implantion technique. Morphine analgesia, as assessed by the tail-flick antinociceptive test, was potentiated in tolerant animals by acute adminstration of pargyline but antagonized by repeated pargyline administration; pargyline produced similar effects in non-tolerant mice and to the same relative degree. Repeated pargyline treatment during morphine pellet implantation enhanced the withdrawal jumping response precipitated by naloxone in dependent mice. Pargyline also, after a single injection, exacerbated jumping in mice undergoing abrupt withdrawal. Neither acute nor chronic pargyline administration altered the brain distribution of injected morphine in non-tolerant mice. It was concluded that pargyline may modify acute morphine actions and withdrawal without materially altering the process(es) involved in the development of tolerance and physical dependence.