Morphine derivatives with diminished opiate receptor potency show enhanced central excitatory activity

doi:10.1016/0006-8993(79)90849-7

Brain Research

Volume 174, Issue 2, 5 October 1979, Pages 263-271

https://doi.org/10.1016/0006-8993(79)90849-7 Get rights and content

Abstract

Central excitatory potency of morphine administered by cerebroventricular infusion is enhanced in derivatives substituted at the 3-position (phenolic group) and/or 6-position (alcoholic group). Morphine-3-glucuronide is several hundred times more potent than morphine in evoking dose-related hyperactive motor behavior which can progress to lethal convulsions. Excitatory potencies in decreasing order are: (1) 3-glucuromide; (2) 3-SO₄; (3) 3-OAc, 6-OAc (heroin); (4) 6-OAc; (5) 3-OAc; (6) 3-OH, 6-OH (morphine); (7) 3-OCH₃ (codeine); (8) 3-OCH₃, 6-OCH₃ (thebaine). Levorphanol, lacking a 6-OH group, is devoid of excitatory actions. In this series of substituted morphines, there is an inverse relationship between opiate receptor binding potency and central excitatory potency, but codeine and thebaine behave anomalously. These findings are compatible with the hypothesis that morphine acts upon a species of receptor which mediates behavioral and EEG excitation and is distinct from the recognized opiate receptor mediating sedation and analgesia.

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To describe the pharmacokinetics, behavioral and physiologic effects and effects on thermal thresholds of morphine, morphine 6-glucuronide (M6G) and morphine 3-glucuronide (M3G) following administration to horses.
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However, no difference in Ki was observed between the two strains. In addition, given that no LPS displacement was observed, it is likely that M3G was displacing [3H]diprenorphine from MOP, which has approximately 1000-fold lower affinity or that M3G was contaminated by a small amount of morphine (Labella et al., 1979; Juni et al., 2006). Our results present a paradox.
Toll-like receptors (TLR) have been proposed as a site of action that alters opioid pharmacodynamics. However, a comprehensive assessment of acute opioid antinociception, tolerance and withdrawal behaviours in genetic null mutant strains with altered innate immune signalling has not been performed. Nor has the impact of genetic deletion of TLR2/4 on high-affinity opioid receptor binding. Here we show that diminished TLR signalling potentiates acute morphine antinociception equally in male and female mice. However, only male TIR8 null mutant mice showed reduced morphine analgesia. Analgesic tolerance was prevented in TLR2 and TLR4 null mutants, but not MyD88 animals. Withdrawal behaviours were only protected in TLR2^−/− mice. In silico docking simulations revealed opioid ligands bound preferentially to the LPS binding pocket of MD-2 rather than TLR4. There was no binding of [³H](-)-naloxone or [³H]diprenorphine to TLR4 in the concentrations explored. These data confirm that opioids have high efficacy activity at innate immune pattern recognition binding sites but do not bind to TLR4 and identify critical pathway and sex-specific effects of the complex innate immune signalling contributions to opioid pharmacodynamics. These data further support the behavioural importance of the TLR-opioid interaction but fail to demonstrate direct evidence for high-affinity binding of the TLR4 signalling complex to ligands.
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Curcuma longa (turmeric) is commonly used as spice and also used to treat fever, cough and febrile convulsions in Nigeria. This study determined the chemical composition of the essential oil of C. longa and evaluated its neuropharmacological activity in mice.
Essential oil of C. longa (EOCL) fresh rhizome was obtained by hydrodistillation and its chemical composition determined by GC–MS. Acute toxicity (LD₅₀) profile of the essential oil was determined orally (p.o.) and intraperitoneally (i.p.); and the EOCL (50–200 mg/kg, i.p.) was evaluated for its behavioural, anxiolytic, sedative and anticonvulsant activities using appropriate models in Albino mice (Vom Strain, Jos, Nigeria).
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The mice received the drugs orally once daily for 29 consecutive days. Thirty minutes after the last treatment, rearing and crossings considered as the central excitatory locomotor behaviors (Ajayi & Ukponmwan, 1994; Labella, Punsky, & Havlicek, 1979) were counted as the numbers of times that the mouse was standing on its hind limb with its forelimbs in the free air or against the wall of the observation cage and crossing to adjacent squares. The numbers of rearing and crossings were counted for 10 min.
Maoyecha tea, a natural non-caffeine and high-theobromine-containing tea variety, is a special tea resource in southern China. The aims of this study were to analyze the changes in quality components of Maoyecha tea during anaerobic treatment, and to investigate whether or not the extract of gamma-aminobutyric acid (GABA) present in Maoyecha tea has the sleep-promoting effect. The results showed that GABA content in Maoyecha tea was increased significantly and reached the standard of GABA tea after anaerobic treatment. The contents of free amino acids and alkaloids were also significantly increased whereas polyphenols and water extract were reduced. At the same time, treatment under vacuum accelerated the transformation of catechins. More importantly, the extract of GABA Maoyecha tea was shown to have the sleep-promoting effect. These neuropharmacological properties are possibly and mainly mediated via the GABAergic neurotransmission.

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^*: Cancer Investigator of the Medical Research Council of Canada.

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Morphine derivatives with diminished opiate receptor potency show enhanced central excitatory activity

Abstract

Life Sci.

Life Sci.

Biochem. Biophys. Res. Commun.

Biochem. Pharmacol.

Effects of cholinergic and anticholinergic drugs and a partial cholinergic agonist on the development and expression of physical dependence on morphine in rat

J. Pharmacol. expt. Ther.

Morphine-6-hemisuccinate as a narcotic analgesic

Life Sci.

Antagonism of the convulsant effects of heroin, d-propoxyphene, meperidine, normeperidine and thebaine by naloxone in mice

J. Pharmacol. expr. Ther.

General anaesthesia induced by intracerebroventricular beta-endorphin

Physiologist

Opiate effects after adrenocorticotropin or β-endorphin injection in the periaqueductal gray matter of rats

Science

Stereospecific and non-stereospecific effects of (+) and (−) morphine: evidence for a new class of receptors?

Science