Reversal of morphine-induced catalepsy in the rat by narcotic antagonists and their quaternary derivatives

doi:10.1016/0028-3908(83)90246-0

Neuropharmacology

Volume 22, Issue 3, Part 1, March 1983, Pages 317-321

https://doi.org/10.1016/0028-3908(83)90246-0 Get rights and content

Abstract

The effects of the pure narcotic antagonists, naloxone and naltrexone, and their quaternary derivatives, methylnaloxon and methylnaltrexone, were examined in reversing the catalepsy induced by morphine in rats. Morphine, 20 mg/kg, induced rigid catalepsy which attained a peak effect (as manifested by duration of catalepsy) at 60–120 min and progressively declined thereafter. Both naloxone and naltrexone, administered subcutaneously 40 min after the injection of morphine, dose-dependently reduced the duration of the catalepsy at doses of 10–30 μg/kg. Methylnaloxone also completely reversed the catalepsy at doses of 1–10 mg/kg, when given subcutaneously. In contrast, the subcutaneous administration of methylnaltrexone only partially reversed the catalepsy at doses up to 56 mg/kg 60–90 min post-morphine. The extent of the reversal of catalepsy produced by methylnaltrexone tended to increase with time. Methylnaltrexone, administered into the cerebral ventricles 70 min after the injection of morphine, completely suppressed the catalepsy with an ED₅₀ of approx. 1μg/kg when tested at 90 min after morphine. These results indicate that opiate-induced catalepsy is predominantly mediated at sites within the central nervous system. Methylnaltrexone is about 10,000 times more potent in reversing catalepsy when administered centrally than when administered peripherally. Thus, methylnaltrexone may be useful in defining sites of opiate action and in therapeutically blocking undesirable peripheral effects of opiate analgesics.

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Cited by (55)

Methylnaltrexone crosses the blood-brain barrier and attenuates centrally-mediated behavioral effects of morphine and oxycodone in mice
2021, Neuropharmacology
Citation Excerpt :
For instance, Brown and Holtzman (1981) demonstrated that i.c.v., but not peripheral administration of MNTX, decreases water intake in water-deprived rats. Similarly, morphine-induced catalepsy was only partially attenuated by peripheral administration of 56 mg/kg MNTX but completely reversed when administered i.c.v. (Brown et al., 1983). We have previously shown accelerated antinociceptive tolerance to morphine in the TNBS model (Komla et al., 2019) and therefore, another objective of our studies was to determine whether inhibition of peripheral opioid receptors could mitigate the development of tolerance in this inflammatory model.
Antagonism of peripheral opioid receptors by methylnaltrexone (MNTX) was recently proposed as a potential mechanism to attenuate the development of opioid analgesic tolerance based on experiments conducted in mice. However, reports indicate that MNTX is demethylated to naltrexone (NTX) in mice, and NTX may subsequently cross the blood-brain barrier to antagonize centrally-mediated opioid effects. The goal of this study was to determine whether MNTX alters centrally-mediated behaviors elicited by the opioid analgesics, morphine and oxycodone, and to quantify concentrations of MNTX and NTX in blood and brain following their administration in mice.
Combinations of MNTX and morphine were tested under acute and chronic conditions in thermal nociceptive assays. Effects of MNTX and NTX pretreatment were assessed in an oxycodone discrimination operant procedure. Blood and brain concentrations of these antagonists were quantified after their administration using liquid chromatography-mass spectrometry.
MNTX dose-dependently attenuated acute and chronic morphine antinociception. MNTX and NTX dose-dependently antagonized the discriminative stimulus effects of oxycodone. MNTX and NTX were detected in both blood and brain after administration of MNTX, confirming its demethylation and demonstrating that MNTX itself can cross the blood-brain barrier.
These results provide converging behavioral and analytical evidence that MNTX administration in mice attenuates centrally-mediated effects produced by opioid analgesics and results in functional concentrations of MNTX and NTX in blood and brain. Collectively, these findings indicate that MNTX cannot be administered systemically in mice for making inferences that its effects are peripherally restricted.
Induction of Fos proteins in regions of the nucleus accumbens and ventrolateral striatum correlates with catalepsy and stereotypic behaviours induced by morphine
2009, Neuropharmacology
Citation Excerpt :
Our findings suggest that a functional imbalance in the activity of patch and matrix projection neurons potentially correlate with morphine-induced motor behaviours. The present study confirmed earlier reports that administration of morphine to drug-naive rats induces catalepsy in drug-naive, but tolerance to this effect develops in rats with a history of morphine exposure (Brown et al., 1983; De Ryck et al., 1980; Olmstead and Franklin, 1994; Wilcox et al., 1983). Our data showed that this tolerance to catalepsy was replaced by an increase in opioid-induced oral stereotyped behaviours consisting of biting, gnawing, and chewing.
A history of intermittent exposures to drugs of abuse can cause long-term changes in acute behavioural responses to a subsequent drug exposure. In drug-naive rats, morphine can elicit intermittent cataleptic postures followed by sustained increases in locomotor activity. Chronic intermittent morphine treatment can reduce catalepsy and increase locomotor behaviour and stereotypy induced by morphine, even after prolonged periods of abstinence. The nucleus accumbens and limbic basal ganglia circuitry are implicated in the expression of various morphine-induced motor behaviours and catalepsy. We examined the effect of intermittent morphine exposure on the distribution of Fos proteins in the basal ganglia following a subsequent morphine challenge administered after a period of drug abstinence. We found that such exposures increased c-Fos induced by a morphine challenge in accumbens core regions that were immunoreactive for the μ-opioid receptor, and this correlated with the frequency of stereotypic behaviours displayed by the rats. We also found that a history of morphine exposures increased c-Fos in the ventrolateral striatum in response to a morphine challenge following 14 d but not 24 h of drug abstinence. In contrast, such a history induced acute Fras in the nucleus accumbens in response to a morphine challenge following 24 h but not 14 d of morphine abstinence. These data provide further confirmation that psychomotor sensitisation induced by repetitive morphine exposure involves long-term neuroadaptations in basal ganglia circuitry particularly at the level of the nucleus accumbens.
The involvement of the μ-opioid receptor in gastrointestinal pathophysiology: Therapeutic opportunities for antagonism at this receptor
2008, Pharmacology and Therapeutics
The localization of opioid receptors and their endogenous peptide ligands within the gastrointestinal (GI) tract and their role in the coordination of propulsion and secretion underscores the importance of opioid receptors in the maintenance of GI homeostasis. The peripherally acting μ-opioid receptor antagonists alvimopan and methylnaltrexone (MNTX) are currently under investigation as therapeutic agents to treat the deleterious GI side effects associated with opioid administration. These compounds have demonstrated efficacy in numerous animal models of GI function, and clinical studies have revealed their efficacy in the treatment of postoperative ileus (POI) and opioid-induced bowel dysfunction. Preservation of opioid-mediated analgesia has been demonstrated for these compounds in both the preclinical and clinical settings. Future studies exploring the benefits of selective antagonism of the peripheral μ-opioid receptor in the treatment of other GI conditions may open new therapeutic opportunities for alvimopan and MNTX.
Involvement of peripheral mechanism in the verapamil-induced potentiation of morphine analgesia in mice
2004, Journal of Pharmacological Sciences
Morphine’s analgesic actions are thought to be mediated through both the central and peripheral nervous systems. L-type calcium channel blockers have been reported to potentiate the analgesic effects of morphine, but the locus of this interaction is not known. In this experiment, we examined the site of verapamil-induced potentiation of morphine analgesia in mice using the quaternary opioid receptor antagonist naloxone-methiodide (NLX-M). Subcutaneous injections of morphine increased locomotor activity and serum corticosterone level, which are mediated by the central nervous system. These central effects were not antagonized by 0.1 mg/kg of NLX-M, whereas this dose of NLX-M partially antagonized the analgesic effect of morphine. Treatment with verapamil potentiated morphine analgesia in a dose-dependent manner. The verapamil-induced potentiation of morphine analgesia was abolished by pretreatment with NLX-M (0.1 and 1 mg/kg). These findings suggest that peripheral mechanisms partially contribute to morphine analgesia and mediate the potentiation of morphine analgesia by verapamil.
Nicotine potentiation of morphine-induced catalepsy in mice
2002, Pharmacology Biochemistry and Behavior
In the present study, effects of nicotine on catalepsy induced by morphine in mice have been investigated. Morphine but not nicotine induced a dose-dependent catalepsy. The response of morphine was potentiated by nicotine. Intraperitoneal administration of atropine, naloxone, mecamylamine, and hexamethonium to mice reduced catalepsy induced by a combination of morphine with nicotine. Intracerebroventricular injection of atropine, hexamethonium, and naloxone also decreased catalepsy induced by morphine plus nicotine. Intraperitoneal administration of atropine, but not intraperitoneal or intracerebroventricular injection of hexamethonium, decreased the effect of a single dose of morphine. It was concluded that morphine catalepsy can be elicited by opioid and cholinergic receptors, and the potentiation of morphine induced by nicotine may also be mediated through cholinergic receptor mechanisms.
A review of the potential role of methylnaltrexone in opioid bowel dysfunction
2001, American Journal of Surgery
Citation Excerpt :
Early experimental studies showed that when administered intravenously, MNTX did not induce withdrawal symptoms in opioid-tolerant dogs at doses as high as 50 mg/kg, whereas naltrexone at 100-fold lower doses elicited signs of withdrawal [12]. Further evidence for MNTX’s lack of central activity was obtained from the inability of subcutaneous MNTX to reverse morphine-induced catalepsy in rats, whereas intracerebrally injected MNTX did so at a 10,000-fold lower dose [23]. The peripheral selectivity of MNTX was superior to that of methylnaloxone and methylnalorphene, as measured by ability to precipitate a withdrawal response in isolated guinea pig ileum from morphine-dependent animals, but not in vivo in morphine-dependent monkeys [24].
Opioids are widely used analgesics in patients with advanced cancer. However, their effectiveness for pain relief is often limited by the most frequently occurring side effect, opioid bowel dysfunction (OBD). Because conventional laxation measures are often ineffective in treating OBD, alternative approaches need to be investigated. Opioid action on the gut appears to be mediated mainly by receptors in the gastrointestinal (GI) tract rather than by those in the central nervous system (CNS). Opioid antagonists, such as naloxone, naltrexone, and nalmefene, have been studied as a means of antagonizing the peripheral effects of opioids, but these agents can enter the CNS and reverse analgesia or cause opioid withdrawal symptoms. Methylnaltrexone (MNTX) is a novel quaternary derivative of naltrexone that does not cross the blood–brain barrier and acts as a selective peripheral opioid receptor antagonist. In normal volunteers, intravenous or oral MNTX reverses opioid-induced reduction in bowel motility without affecting analgesia. Bioavailability of MNTX is low after oral administration, and plasma levels do not correlate with its actions in the gut, suggesting a predominantly local luminal action of MNTX on the gut. In patients receiving long-term opioid therapy, MNTX administered intravenously or orally was effective in reducing the delay in oral-cecal transit and eliciting laxation responses in all subjects without causing withdrawal symptoms. MNTX is a peripherally selective opioid antagonist that may have clinical utility in managing OBD with minimal adverse effects.

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Reversal of morphine-induced catalepsy in the rat by narcotic antagonists and their quaternary derivatives

Abstract

Life Sci.

Eur. J. Pharmac.

Neuropharmacology

Neuropharmacology

Pharmac. Biochem. Behav.

Observations on the neuropharmacology of morphine and morphine-like analgesia

Archs int. Pharmacodyn. Ther.

On catalepsy and catatonia and the predictability of the catalepsy test for neuroleptic activity

Psychopharmacologia

A role for the amygdala in the development of the cataleptic and stereotypic actions of the narcotic agonists and antagonists in the rat

Psychopharmacologia