Alternations in the efficacy of naloxone induced by stress, cyclic adenosine monophosphate, and morphine tolerance

doi:10.1016/0014-2999(76)90107-2

European Journal of Pharmacology

Volume 39, Issue 1, September 1976, Pages 1-10

https://doi.org/10.1016/0014-2999(76)90107-2 Get rights and content

Abstract

Pretreatment of mice with a single injection of morphine or by chronic implantation of morphine pellets increased the ability of naloxone to antagonize the antagonize the analgetic effects of morphine. However, this increased effectiveness of naloxone was also produced by pretreatment with diethylether, ACTH, corticosterone or dexamethasone. Thus, the increased potency of naloxones observed after pretreatment witn narcotics may be due, at least in part, to those pretreatments on the pituitary—adrenal axis. In addition, in animals made highly tolerant and dependent by cAMP administration during morphine pellet implantation, the narcotic antagonist potency of naloxones was similar to that of untreated animals.

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Chronic opioid antagonist administration increases opioid binding sites and potentiates behavioral responses to morphine. Conversely, chronic opioid agonist administration attenuates behavioral responses to morphine, though this is not necessarily accompanied by a parallel loss of binding sites. We examined the possibility that the in vivo affinity of the μ receptors might be altered as a consequence of the continuous administration of either naloxone or morphine. Rats were implanted sc with naloxone- or morphine-filled osmotic pumps; control animals were implanted with sham pumps. One week later, 24 hr after removing the osmotic pumps, cumulative dose-response curves for fentanyl analgesia were generated in the presence of 0.0, 0.03, 0.1, or 0.3 mg/kg naltrexone, using a tail-flick procedure. The analgesic ED₅₀ (with 95% C.L.) of fentanyl in sham implanted animals, following saline pretreatment was 0.027 mg/kg (0.019, 0.039). The potency of fentanyl was decreased in rats infused with morphine, ED₅₀ = 0.051 mg/kg (0.028, 0.093), and increased in rats that received naloxone, ED₅₀ = 0.018 mg/kg (0.015, 0.022). The mean apparent pA₂ value for naltrexone (with 95% C.L.) in the control group was 7.7 (7.5, 7.9). No differences were detected in animals that had received either naloxone or morphine for 7 days, pA₂=7.8 (7.5, 8.1) and (7.3, 7.6), respectively. Our results indicate that there is no change in the apparent affinity of the μ-receptor following continuous exposure to either an opioid agonist or antagonist, at a time when the analgesic potency of the agonist is decreased or increased, respectively.
Quantitative analysis of the interaction between the agonist and antagonist isomers of picenadol (LY150720) on electric shock titration in the squirrel monkey
1984, European Journal of Pharmacology
The opioid mixed agonist-antagonist picenadol (LY150720) is a racemate whose resolution results in a highly stereospecific separation of opioid agonist and antagonist activity. Attenuation of the antinociceptive effects of the agonist (dextro) isomer LY136596 by the antagonist (levo) isomer LY136595 was evaluated quantitatively in squirrel monkeys responding under a schedule of electric shock titration through the use of a dose-ratio analysis. LY136596 (0.3–3.0 mg/kg) produced a dose-related increase in the intensity at which monkeys maintained the shock. Increases in shock intensity produced by LY136596 were antagonized by LY136596 (0.1–10.0 mg/kg); dose-response curves for LY136596 were shifted to the right in a parallel manner by increasing doses of LY136595. An apparent pA₂ (Schild) plot obtained from these data yielded a line with a slope of −0.60 ± 0.05 and an apparent pA₂ value of 5.67 ± 0.07. These data support previous suggestions that the antinociceptive activity of picenadol (LY150720) resides in the d-isomer (LY136596) and that the l-isomer (LY136595) acts to limit the analgesic efficacy of the racemate.
Effects of Mu- and kappa-opioid receptor agonists on urinary output in mice
1983, Pharmacology, Biochemistry and Behavior
The effects of ethylketazocine, morphine, bremazocine and naloxone were determined on urinary output and weight loss in Cox mice. Morphine and fentanyl were also studied in Harlan mice. Bremazocine, ethylketazocine and morphine markedly increased urinary output and weight loss within 5 hr after injection. Naloxone antagonized the diuretic actions of morphine (5 mg/kg) and bremazocine (0.06 mg/kg) over a similar dose range (0.3–10 mg/kg). By comparison with the other agonists, fentanyl had little effect on urinary output or weight loss. These results suggest that kappa agonist activity increases urinary output in mice just as reported for rats. The data also suggest that in mice morphine has some kappa agonist activity, whereas fentanyl does not.
The hypothalamus exhibits electrophysiologic evidence for morphine tolerance and dependence
1982, Experimental Neurology
The electrophysiologic effects of morphine (10 mg/kg) were studied in naive rats and after chronic morphine treatment for 5 days. Spontaneous multiunit activity was recorded from the ventromedial hypothalamus of unanesthetized, freely behaving rats implanted previously with permanent electrodes. In the naive condition, firing rates were altered by morphine in 60 of 73 multiunits. After development of tolerance, 28 of multiunits responded to the morphine challenge dose, in 22 of which the direction of change was opposite that observed in the naive condition. The other six were not affected by morphine on day 1 of the experiment and became sensitive to the morphine challenge dose only after the animal had become physically dependent on morphine. Predrug baseline activity in morphine physically dependent rats was altered in 23 recordings compared to the predrug activity obtained in morphine naive animals. Based on effects of morphine and naloxone, responses could be grouped into six electrophysiologic patterns which provide for separation of tolerance from the dependence phenomena.
The effect of prostaglandin E<inf>2</inf> on increased naloxone potency induced by morphine pretreatment
1981, European Journal of Pharmacology
Pretreatment with prostaglandin E₂ caused an increase in naloxone potency while the antinociceptive effect of morphine remained unaffected. These effects of prostaglandin E₂ were not blocked by concomitant administration of naloxone in the pretreatment. Furthermore, when prostaglandin E₂ was given together with morphine as pretreatment, the resulting naloxone antagonism measured was higher than those induced by pretreatment with the individual drugs. It is suggested that the induction of increased naloxone potency is likely to be mediated through a prostaglandin-linked process.
Enhancement of etorphine brain concentrations and changes in etorphine-naloxone pA<inf>2</inf>; values in morphine-pretreated mice
1981, Biochemical Pharmacology
We had shown earlier that pretreatment of mice with a single dose of morphine sulfate enhanced the concentration of naloxone in the brain, and, therefore, the effect of this pretreatment on brain disposition of the narcotic agonist etorphine was examined for similar effects. Three hours after pretreatment with morphine, [³H]etorphine was administered subcutaneously, and its brain concentrations were determined as a function of time. Etorphine brain concentrations were higher in morphinethan in saline-pretreated animals at 5, 15, 20 and 30 min. This enhancement of brain concentrations was not associated with a change in the analgesic ED₅₀ for etorphine. Morphine pretreatment in mice has been reported by others to increase the affinity of the antagonist receptor site for naloxone, as demonstrated by an increase in the in vivo apparent pA₂ value for a morphine-naloxone interaction. In the present study, the morphine pretreatment decreased the etorphine-naloxone apparent pA₂ value in the direction opposite to that observed for the morphine-naloxone interaction. The results are discussed relative to a morphine-induced change in the disposition of etorphine in the brain, or to a morphine-induced alteration in morphine, etorphine and naloxone interactions at agonist and antagonist binding sites.

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Alternations in the efficacy of naloxone induced by stress, cyclic adenosine monophosphate, and morphine tolerance

Abstract

European J. Pharmacol.

Biochem. Pharmacol.

Life Sci.

Some qualitative uses of drug antagonism

Brit. J. Pharmacol.

Studies on the mechanism of stimulation of ACTH secretion with the aid of morphine as a blocking agent

Endocrinol.

Relative degree of tolerance to morphine sulfate and methadone hydrochloride in the rat and the interaction of dexamethasone

Arch. Intern. Pharmacodyn.

Quantitative studies of the antagonism by nalorphine of some of the actions of actions morphine-like analgesic drugs

Brit. J. Pharmacol.

Corticosteroid feedback control of stress-induced ACTH secretion

A method for determining loss of pain sensation

J. Pharmacol. Exptl. Therap.

Effect of etahnol on plasma corticosterone levels

J. Pharmacol. Exptl. Therap.

Hypothalamus: anterior pituitary gland

Studies on the mechanism of pituitary—adrenal activation by morphine

Brit. J. Pharmacol.

Biostatistics

Antagonism of morphine analgesia by adenine, adenosine and adenine nucleotides

Effects of divalent cations, cation chelators, and an ionophore on morphine analgesia and tolerance

J. Pharmacol. Exptl. Therap.

Antinociceptive effects of lanthanum and cerium in non-tolerant and morphine tolerant-dependent animals

J. Pharmacol. Exptl. Therap.