Quasi-morphine Withdrawal Syndrome Research Articles

Endorphinergic Attenuation of Distress by Concomitantly Enhancing Endogenous Opioid Release and Switching Opioid Receptor Signaling from an Excessively Excitatory to a Normal Inhibitory Mode

The endogenous opioid system plays a significant role in the modulation of distress in many psychiatric, neurologic, and neurodevelopmental disorders. Many clinical distress symptoms show similarities to the excitatory autonomic withdrawal effects in chronic opioid-dependent animals and humans, as well as to the “quasi-morphine withdrawal syndrome” evoked in naive rodents shortly after acute systemic injection of cyclic AMP-phosphodiesterase (cAMP-PDE) inhibitors. These symptoms result from excessive excitatory opioid receptor signaling and increased endorphin release. Pharmacologic analyses of the remarkably plastic bimodal (excitatory/inhibitory) signaling functions of opioid receptors have utilized microelectrode recordings from opioid-sensitive neurons in tissue cultures of mouse sensory ganglia and hot-water tail-flick assays in mice. These studies led to development of specific chemical formulations that switch opioid receptor signaling from an excessively excitatory to a normal inhibitory mode. Critical combinations of cAMP-PDE inhibitors that release endorphins plus specific agents that switch opioid receptors from excitatory Gs-coupled to inhibitory Gi/Go-coupled signaling were shown to attenuate hyperalgesia and distress evoked by diverse chemical stressors in mouse tail-flick assays. Both the “quasi-morphine withdrawal syndrome” in naive rodents as well as the excitatory withdrawal effects in chronic, opioid-dependent animals and humans may be manifestations of a common Endorphinergic Distress Syndrome (EDS). We suggest that many distress symptoms are caused by EDS, a dysfunctional imbalance in the endogenous opioid system, consisting of abnormal endorphin levels, together with opioid receptors predominately in their excitatory mode. Therefore, concomitantly enhancing endogenous opioid release and switching excessive excitatory opioid receptor signaling to inhibitory signaling can attenuate these distress symptoms. Trials of a critically formulated oral preparation, containing both endorphin enhancers and opioid receptor switchers, have resulted in long-term anxiolytic efficacy and enhanced calm and mental clarity in large numbers of individuals with distress symptoms. These endorphinergic formulations may provide treatment for the emotional and physical distress associated with many psychiatric, neurologic, and neurodevelopmental disorders.

Absence of quasi-morphine withdrawal syndrome in adenosine A2A receptor knockout mice

Caffeine and other methylxanthines induce behavioral activation and anxiety responses in mice via antagonist action at A2A adenosine receptors. When combined with the opioid antagonist naloxone, methylxanthines produce a characteristic quasi-morphine withdrawal syndrome (QMWS) in opiate-naive animals. The aim of this study was to establish the role of A2A receptors in the quasi-morphine withdrawal syndrome induced by co-administration of caffeine and naloxone and in the behavioral effects of caffeine. We have used A2A receptor knockout (A(2A)R(-/-)) mice in comparison with their wild-type and heterozygous littermates to measure locomotor activity in the open field and withdrawal symptoms induced by caffeine and naloxone. Naïve wild-type and knockout mice were also examined for enkephalin and dynorphin mRNA expression by in situ hybridization and for mu-opiate receptor by ligand binding autoradiography to check for possible opiate receptor changes induced by A2A receptor inactivation. Caffeine increases locomotion and anxiety in wild-type animals, but it has no psychomotor effects in A(2A)R(-/-) mice. Co-administration of caffeine (20 mg/kg) and naloxone (2 mg/kg) resulted in a severe quasi-morphine withdrawal syndrome in wild-type mice that was almost completely abolished in A(2A)R(-/-) mice. Heterozygous animals exhibited a 40% reduction in withdrawal symptoms, suggesting that there is no genetic/developmental compensation for the inactivation of one of the A(2A)R alleles. A(2A)R(-/-) and wild-type mice have similar levels of striatal mu-opioid receptors, thus the effect is not due to altered opioid receptor expression. Our results demonstrate that A2A receptors are required for the induction of quasi-morphine withdrawal syndrome by co-administration of caffeine and naloxone and implicate striatal A2A receptors and mu-opiate receptors in tonic inhibition of motor activity in the striatum.

Long-term effects of neonatal exposure to isobutylmethylxanthine

An acute model of morphine withdrawal was used to determine if neonatal exposure to 3-isobutyl-1-methylxanthine (IBMX) would cause alterations in the expression of withdrawal in the adult rat. IBMX induces a quasi-morphine withdrawal syndrome (QMWS), which is almost identical to true morphine withdrawal both behaviorally and neurochemically. Transient IBMX treatment during infancy (on days 7-10 of life) caused an attenuated suppression of fixed ratio (FR) responding during acute morphine withdrawal in adulthood; however, there appeared to be no attenuation of withdrawal-induced hypothermia. The attenuated behavioral response was not due to an altered ability to express withdrawal, as these rats did not react differently to various doses of IBMX plus naloxone (i.e., varying severities of quasi-morphine withdrawal) in adulthood. Coadministration of the serotonin (5-HT) antagonist mianserin with IBMX in the neonate prevented the effects of IBMX. Both the mianserin-treated and the IBMX plus mianserin-treated groups had increased levels of [3H]naloxone binding in brainstem, while IBMX treatment alone apparently had no significant effect. None of the neonatal drug treatments affected [3H]naloxone binding in frontal cortex. Thus, the long-term effects of IBMX on the opioid withdrawal response cannot be explained by changes in the number of opioid binding sites (labelled with [3H]naloxone) within the brain. The results indicate that exposure to a methylxanthine, and thus quasi-morphine withdrawal, during development results in long-lasting alterations of a system which is involved in opioid withdrawal. Because coadministration of mianserin prevented the effects of IBMX, 5-HT and 5-HT2 receptors are implicated in these effects.

Long-term effects of neonatal exposure to isobutylmethylxanthine

Pregnant women regularly ingest the methylxanthines, caffeine and theophylline, during pregnancy and lactation. Also, theophylline is used to treat apnea in premature infants. In this study, rat pups were treated with 3-isobutyl-1-methylxanthine (IBMX), on days 7-10 of life. Transient IBMX treatment during infancy caused a retardation of acquisition of a delayed reinforced autoshaped lever touch response in adulthood. Treated rats required more trials to learn the task, but did not show altered exploratory activity in the operant chambers. Coadministration of the serotonin (5-HT) antagonist mianserin with IBMX was able to attenuate significantly the effects of IBMX in both males and females, even though mianserin treatment alone caused an apparent learning deficit in the males. The results indicate that 5-HT and 5-HT receptors are important during development for normal expression of a specific cognitive function later in life. Furthermore, a 5-HT system appears to play a role in the mechanism whereby perinatal methylxanthine exposure could lead to learning impairments or other undesirable behavioral consequences. The use of IBMX in developing rats may also offer a model for studying the long-term consequences of the expression of opioid withdrawal during the neonatal period, since this agent induces a quasi-morphine withdrawal syndrome (QMWS) in mature rats. It is of interest that mianserin can block or attenuate effects of both quasi- and true morphine withdrawal.

The serotonin2 antagonist ritanserin blocks quasi-morphine withdrawal at a time when mianserin is no longer effective

A quasi-morphine withdrawal syndrome (QMWS), produced in opiate-naive rats with an injection of isobutylmethylxanthine (IBMX) and the opioid antagonist naloxone, allows one to study the expression of opiate withdrawal in the absence of the acute or chronic effects of opiates and the adaptive processes termed dependence. The allegedly selective and long-acting serotonin2 (5-HT2) antagonist ritanserin attenuated the QMWS-induced suppression of fixed ratio (FR) operant responding, which is a sensitive measure of the expression of a QMWS. When administered 30 min prior to precipitation of the QMWS, the lowest dose of ritanserin tested (0.158 mg/kg) was the most effective in blocking the expression of withdrawal; however, there was not complete reversal of the behavioral suppression. Acutely, the two higher doses of ritanserin tested (2.5 and 10 mg/kg) suppressed responding when given alone. This may have masked their ability to attenuate a QMWS. At a dose of 2.5 mg/kg, ritanserin completely blocked the QMWS-induced suppression of responding 24 h post-administration, at a time when its actions at other receptors (e.g., alpha 2) have dissipated. At an equivalent dose, the shorter-acting 5-HT2 antagonist mianserin was unable to attenuate the QMWS-induced suppression of FR operant responding 24 h post-administration. The 5-HT2 antagonists reportedly produce a paradoxical down-regulation of 5-HT2 binding sites upon chronic treatment, rather than the expected supersensitivity. Chronic treatment with ritanserin (2.5 mg/kg/day for 7 days), but not mianserin (same regimen), attenuated a QMWS 24 h after the final injection, thus supporting with a functional measure, the down-regulation of such binding sites by ritanserin.(ABSTRACT TRUNCATED AT 250 WORDS)

Modification of quasi-morphine withdrawal with serotonin agonists and antagonists: evidence for a role of serotonin in the expression of opiate withdrawal

Methylxanthines produce a quasi-morphine withdrawal syndrome (QMWS) in opiate naive rats. Additionally, methylxanthine-induced suppression of conditioned behavior in rats is reversed by the alpha 2 adrenergic agonist clonidine which also attenuates true opiate withdrawal and the QMWS. Therefore, the operant behavioral effects of 3-isobutyl-1-methylxanthine (IBMX) provide a model with which to study mechanisms involved in the expression of opiate withdrawal. In order to examine the role of serotonin (5-HT) in the rate-decreasing effects of IBMX on operant behavior, the 5-HT precursor 5-hydroxytryptophan, and 5-HT reuptake blocker fluoxetine were administered in combination with IBMX to rats performing a fixed-ratio 30 operant for food reinforcement. Both drugs failed to reverse the behavioral suppression caused by relatively low doses of IBMX, suggesting that elevated 5-HT neurotransmission contributes to, rather than attenuates, the QMWS. The relatively selective 5-HT2 antagonists mianserin and pirenperone blocked the IBMX-induced suppression, whereas the classic 5-HT antagonist methysergide had no effect. The results indicate that the operant behavioral effects of IBMX and possibly the QMWS may be mediated by serotonergic mechanisms.

Age- and sex-related induction of excessive grooming and “wet-dog” shakes by the codeinone RX 336-M in the rat

Peripheral administration of the dihydrocodeinone RX 336-M (6 mg/kg) stimulated vigorous "wet-dog" shakes and excessive grooming in young drug-naive rats. The effects of RX 336-M were greater in younger than in older animals of both sexes, and were greater in 39-day-old male rats than in female rats of the same age. In a second experiment, female rats were pretreated with testosterone benzoate (1 mg/kg/day) for 1 week prior to testing the effects of RX 336-M at 39 days of age. The sex hormone pretreatment enhanced the ability to RX 336-M to induce "wet-dog" shakes and excessive grooming in female rats. The results suggest that both sex- and hormone-dependent developmental status are critical in the display of the so-called "quasi-morphine withdrawal syndrome." The results imply, and are consistent with previous studies which suggest, that different neural mechanisms underlie the behavioral responses induced by ACTH and RX 336-M.

The quasi-morphine withdrawal syndrome: Effect of cannabinol, cannabidiol and tetrahydrocannabinol

Δ-9-tetrahydrocannabinol (THC), the main psychoactive principle of cannabis, has been shown to attenuate the exhibition of signs of the quasi-morphine withdrawal syndrome in rats. Cannabinol (CBN) showed the same activity but required a dosage of approximately eight times that of THC to produce and equivalent effect. Cannabidiol was without effect at the dosage levels used. The efficacy of these cannabinoids and the potency differencess recorded in this study are in accord with their effects onother behaviours, both in experimental animals and in man. The activity of THC and CBN was not affected by the narcotic antagonist, naloxone.

In vivo and in vitro studies with agents that cause quasi-morphine withdrawal syndromes

Compounds that elicit a “quasi-morphine withdrawal syndrome” (QMWS) after acute administration to rats constitute a new class of behavior-modifying agent. In studying the pharmacological bases of quasi-opiate withdrawal syndromes, we found that the dihydrocodeinone, RX 336-M, a standard QMWS-inducing agent, caused a naloxone-insensitive increase in twitch tension on the field-stimulated rat vas deferens preparation. In contrast, IBMX (3-isobutyl-l-methylxanthine), the historical inducer of quasi-abstinence in rats, gave a naloxone-insensitive decrease in twitch tension. Tolerance developed to the “wet-dog” shakes elicited by twice-daily s.c. injections of RX 336-M or IBMX in rats for 5 or 15 days, respectively. The parallel development of tolerance to the in vitro effects of these compounds could not be demonstrated

Clonidine suppresses methylxanthine induced quasi-morphine withdrawal syndrome

The effects of the alpha-2 adrenergic agonist, clonidine, on the “quasi-morphine withdrawal syndrome” (QMWS) were examined in drug naive rats. The QMWS was induced by combined systemic administration of iso-butyl-methylxanthine (IBMX: 15 mg/kg, IP) and naloxone (1 mg/kg, IP). Pretreatment with clonidine (50 μg/kg, IP) significantly decreased the incidence of 11 out of 16 withdrawal signs. Since clonidine suppresses signs and symptoms of true morphine withdrawal, the suppression of methylxanthine effects demonstrates an additional similarity of the QMWS to true morphine withdrawal. These ressults suggest that a significant common neural mechanism of both the QMWS and true morphine withdrawal is affected by clonidine.

Mechanism of quasi-morphine withdrawal behaviour induced by methylxanthines

Of 7 phosphodiesterase inhibitors tested for ability to induce a quasi-morphine withdrawal syndrome (QMWS) in opiate-naive rats, five were effective in a dose-related way. These, in descending order of potency, were IBMX, ICI-63197, RO-201724, theophylline and caffeine. Their potencies in inducing a QMWS correlated significantly (P < 0.05) with those in inhibiting low Km cyclic AMP phosphodiesterase of rat brain homogenate. There was no correlation with potencies in inhibiting cyclic GMP phosphodiesterase.

The attenuation of delta 9-tetrahydrocannabinol and morphine of the quasi-morphine withdrawal syndrome in rats.

The effect of delta 9-tetrahydrocannabinol (THC), morphine, haloperidol and chlordiazepoxide on the exhibition of the signs of the quasi-morphine withdrawal syndrome was studied in rats. In preliminary studies approximately equi-sedative doses of these drugs were chosen. Morphine and THC produced a very similar degree of suppression of the signs of the quasi-morphine withdrawal, but unlike morphine, the effects of THC were not reversed by the narcotic antagonist, naloxone. The dopamine receptor antagonist, haloperidol, produced a moderate suppression of the withdrawal syndrome and chlordiazepoxide was without significant effect. It is concluded that THC is of very similar potency to morphine in suppressing the quasi-morphine withdrawal syndrome, but its activity in this regard does not appear to be dependent upon the availability of opiate or dopamine receptors, nor is it due to sedation alone.