H. H. Loh

Effects of clonidine on morphine withdrawal signs in the rat

The influence of clonidine on the naloxone-induced withdrawal signs, escape attempts and precipitated shakes, was studied in morphine-dependent rats. Clonidine injected i.p. or intraventricularly (i. vent.) inhibited precipitated shakes and potentiated escape attempts induced by naloxone in morphine-dependent rats. Under pentobarbital anesthesia, precipitated shakes and ice water-induced wet shakes were inhibited by clonidine and norepinephrine. Clonidine injected i. vent. reduced body temperatures in morphine-dependent rats but not in placebo pellet-implanted rats. We suggest that clonidine modulates morphine withdrawal signs by potentiating the behavior associated with heat dissipation (escape attempts) and inhibiting the behavior associated with heat gain mechanisms (precipitated shakes). These effects may occur via stimulation of central noradrenergic mechanisms.

Thyrotrophin-releasing hormone and shaking behaviour in rat.

THYROTROPHIN-RELEASING hormone (TRH) produces behavioural effects in experimental animals1 and may have psychoactive properties in man2–5. Winokur and Utiger6 and Brownstein et al.7 have described the distribution of TRH in rat brain, suggesting that TRH has a modifying role in synaptic functions in addition to its effect on the pituitary. The behavioural effects of endogenous TRH release in the brain are not known; however, Prange et al.8 noted that the systemic administration of TRH to pentobarbital-anaesthetised rats resulted in lacrimation, paw tremor and a peculiar shaking movement of the head and trunk. These behavioural effects were also obtained in partially anaesthetised rats following intracisternal injection of 10 µg TRH per animal. The TRH-induced shaking was particularly interesting because we have observed this behaviour as a characteristic sign of morphine abstinence in the anaesthetised rat9. Here, we have studied the central sites of TRH-induced shaking to determine if these sites parallel the endogenous distribution of TRH in the rat brain and also to determine if these sites correspond to brain areas where morphine withdrawal shakes are obtained.

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.

Opiate binding to cerebroside sulfate: a model system for opiate-receptor interaction.

Abstract Cerebroside sulfate was shown to bind etorphine and levorphanol with high affinity. The relative potency of narcotic analgesics in preventing the binding of levorphanol to cerebroside sulfate correlated well with their reported analgetic activity. The data indicate similarities between cerebroside sulfate and a purified opiate receptor from mouse brain which has been reported to be a proteolipid. Some preliminary animal data also imply the involvement of CS in opiate action We, therefore, propose that CS may serve as a useful “receptor” model for the study of opiate-receptor interaction in vitro .

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.

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.

The increase in brain tryptophan caused by amphetamine-like drugs: Correlation with an increase in body temperature

Abstract The effects of amphetamine, hyperthermia and increased serum unesterified fatty acids (UFA) were considered as having possible roles in the amphetamine-induced increase in brain tryptophan (Trp) levels. The change in brain Trp of male Sprague-Dawley rats 1 hour after the administration of various amphetamine-like drugs (50 μmoles/kg) correlated with the change in rectal temperature (r = 0.89) but not with the increase in serum UFA (r = 0.04). Also, increases in UFA did not correlate with increases in temperature (r = 0.01). The amphetamine-induced increase in brain Trp was not accompanied by significant changes in the levels of aromatic amino acids in serum. The amphetamine-induced increase in brain Trp also correlated with the increase in body temperature in six strains of mice (r = 0.93). No significant increases in serum UFA were observed in mice 1 hour after the administration of d1-amphetamine (50 μmoles/kg).

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.

Brain lesions modifying the abstinence signs in morphine-dependent rats

Abstract Abstinence signs, mastication (teeth chattering), myoclonic twitch and repetitive shaking movements (wet shakes) were precipitated by naloxone and were recorded electromyographically from the suprahyoideal muscle in morphine-dependent rats anaesthetized with urethane. Transverse brain lesions were made bilaterally with an iridectomy knife in urethane anaesthetized morphine-dependent rats. Lesions at the level of the anterior commissure did not inhibit the myoclonic twitch and mastication but markedly potentiated wet shakes. Lesions which separated the connection between the corpus striatum and the thalamus completely abolished mastication, but the twitching activity and wet shakes were not affected. Mid-thalamus lesions did not inhibit wet shakes and mastication, but the myoclonic twitch activity was markedly reduced. Lesions at the mid-collicular level abolished all of the three activities observed. The results suggest that different precipitated withdrawal signs may originate from different brain areas.

On the specificity of trypsin (EC 3.4.4.4) of nerve ending particles to inhibit norepinephrine transport.

The Na+ and energy dependent uptake of norepinephrine into cortical rat brain homogenates or purified nerve ending particles (NEP) is reduced by prior trypsin treatment. In contrast, the uptake of dopamine, serotonin, choline and γ‐aminobutyric acid is markedly less sensitive to the effect of trypsin. Kinetic analyses indicate that the trypsin‐induced decrease of norepinephrine uptake is non‐competitive. In the dose range studied, trypsin did not appreciably alter the protein content or morphology of NEP. However, in a dose related fashion, trypsin decreased the glycoprotein content of NEP measured as the loss of protein bound N‐acetylneuraminic acid.