Morphine Withdrawal In Rats Research Articles

Respiratory Control of Sympathetic Nerve Activity During Naxolone-Precipitated Morphine Withdrawal in Rats

Respiratory Control of Sympathetic Nerve Activity During Naxolone-Precipitated Morphine Withdrawal in Rats

Lesions of the dorsomedial amygdala, but not the nucleus accumbens, reduce the aversiveness of morphine withdrawal in rats.

Small lesions of the dorsomedial amygdala reduced the magnitude of the conditioned place aversion produced by naltrexone-precipitated morphine withdrawal, whereas large lesions of the ventral nucleus accumbens had no effect. This finding that the dorsomedial amygdala, which has not been implicated in opiate reward, is involved in mediating the aversiveness of opiate withdrawal is consistent with data indicating that amygdala lesions reduce the aversiveness of a variety of aversive events. In contrast, the nucleus accumbens, which is involved in mediating the rewarding effects of opiates, does not appear to be critically involved in mediating the aversive effects of opiate withdrawal. Together, these findings suggest that the neural structures that mediate the rewarding effects of opiates may be at least partially distinct from the structures that mediate the aversive effects of opiate withdrawal.

In vivo monoamine release during naloxone-precipitated morphine withdrawal.

There is much evidence from animal work suggesting that the release of noradrenaline (NA) in the brain increases during naloxone-precipitated morphine withdrawal, but the evidence in favour of changes in release of 5-hydroxytryptamine (5-HT) and dopamine (DA) is contradictory. Here we demonstrate, using in vivo microdialysis, that whilst there is a considerable increase (300%) in release of NA in hippocampus precipitated by naloxone in morphine-dependent rats, there is no change in the release of either 5-HT (in hippocampus) or DA (in nucleus accumbens). These results are consistent with suggestions that the symptoms of morphine withdrawal in rats are due primarily to an increase in central NA release.

Long-lasting reciprocal changes in striatal dopamine and acetylcholine release upon morphine withdrawal

In superfused rat striatal slices, the electrically evoked release of [ 3]dopamine was reduced by about 30% and that of [ 14C]acetylcholine was enhanced by about 25% no less than 3 weeks after morphine withdrawal in rats chronically treated with the opiate for 6 days. The lasting nature of the reduced dopamine release at the level of dopaminergic nerve terminals and the concomittant enhanced excitability of neurons tonically inhibited by released dopamine, such as cholinergic interneurons, could play an important role in the maintenance of opiate dependence.

Role of the adrenal gland in the thermal response to morphine withdrawal in rats.

Administration of naloxone to morphine-dependent rats results in an elevation of tail skin temperature and a fall in core temperature. Previous studies have demonstrated a role of the adrenal gland in the thermal responses that accompany morphine withdrawal in the rat. In the present study, experiments were designed to determine if the duration of adrenalectomy significantly influenced the thermal response observed in morphine withdrawal. In addition we evaluated the influence of the adrenal medulla and glucocorticoid replacement in adrenalectomized rats in mediating the thermal responses of the morphine-dependent rat. Ovariectomized rats were addicted to morphine and subsequently withdrawn by administration of naloxone. This treatment results in a significant rise in tail skin temperature and subsequent fall in colonic temperature. These thermal responses were not observed in morphine-naive rats. Adrenalectomy resulted in a significant attenuation of the rise in tail skin temperature associated with withdrawal. This reduced tail skin temperature response was not different among animals adrenalectomized for 1, 7, 14, 21, or 28 days. Likewise, the moderate increase in core temperature associated with morphine treatment was not observed in the adrenalectomized rats. Serum corticosteroid determinations confirmed the loss of the adrenal steroids in the adrenalectomized rats. In a subsequent experiment it was determined that adrenal demedullation did not reduce the tail skin temperature response during morphine withdrawal, and corticosteroids restored the naloxone-induced surge in tail skin temperature in morphine-dependent, adrenalectomized rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of ibogaine on acute signs of morphine withdrawal in rats: Independence from tremor

Because of the claim that ibogaine suppresses the symptoms of “narcotic withdrawal” in humans, the effect of ibogaine on naltrexone-precipitated withdrawal signs in morphine-dependent rats was assessed. Morphine was administered subcutaneously through implanted silicone reservoirs for 5 days. Ibogaine (20, 40 or 80 mg/kg, i.p.) or saline was administered 30 min prior to challenge with naltrexone (1 mg/kg, i.p.) and withdrawal signs were counted for the following 2 hr. Ibogaine (40 and 80 mg/kg) significantly reduced the occurrence of four signs (wet-dog shakes, grooming, teeth chattering and diarrhea) during naltrexone-precipitated withdrawal; three other signs (weight loss, burying and flinching) were unaffected. Ibogaine induces head and body tremors lasting for 2–3 hr and the tremors might have interfered with the expression of opioid withdrawal. To examine this issue, another experiment was conducted in which ibogaine (40 mg/kg) or saline was administered 4 hr prior to challenge with naltrexone. Although there was a complete absence of tremors, ibogaine still significantly reduced the occurrence of the same four signs of withdrawal.

O-061 - Negative correlation of plasma morphine concentration with plasma corticosterone level during morphine withdrawal in rats

O-061 - Negative correlation of plasma morphine concentration with plasma corticosterone level during morphine withdrawal in rats

Ultrasounds during morphine withdrawal in rats

Ultrasounds (US) in rats may communicate affective states, as they occur only in highly significant situations such as maternal care, sex and aggression. Withdrawal from morphine is a manipulation which dramatically alters autonomic, somatic and motor functions; the present experiment demonstrated the production of US in this context and the influence of previous social experience in their production. Sixty male Long-Evans rats with distinct social experiences (social inexperience, defeat or copulation) underwent 72 h of continuous morphine exposure (4 x 75 mg morphine or placebo pellets) and subsequent withdrawal. The rats were observed for 10 min in equally treated pairs and while solitary at 6, 24 and 96 h after pellet removal. US were emitted by all groups and consisted primarily of two distributions of pure tone whistles with little frequency modulation: 1-2 s 21-25 kHz ("low") signals and the more prevalent 0.02-0.1 s 44-52 kHz ("high") signals. Morphine withdrawn rats lost weight, displayed wet dog shakes, were hypoactive and emitted threefold more US vocalizations with a fourfold greater duration than placebo controls. Defeat-experienced morphine withdrawn rats were more hypoactive than either socially inexperienced or copulatory experienced rats while increasing vocalization rates and total duration. This increased duration of ultrasounds included a shift in the distribution of individual US durations from less than 0.3 s to greater than 1.0 s. US are readily emitted at high rates in morphine withdrawn laboratory rats, which may implicate an opioid involvement in their generation.(ABSTRACT TRUNCATED AT 250 WORDS)

Profound depression of mesolimbic dopamine release after morphine withdrawal in dependent rats

We used brain dialysis to study the changes in dopamine release in the mesolimbic ventral striatum elicited by morphine withdrawal in rats treated with morphine every 12 h for 15 days

Mechanisms Mediating the Thermal Response to Morphine Withdrawal in Rats

Studies were undertaken to evaluate the role of peripheral adrenergic mechanisms and the adrenal gland in the thermal responses which accompany morphine withdrawal in the rat. Ovariectomized rats were addicted to morphine and subsequently withdrawn by administration of naloxone. This treatment resulted in a significant rise (5-6 degrees C) in tail skin temperature (TST) and fall in colonic temperature (2-4 degrees C). Systemic administration of clonidine (0.5 mg/kg) completely suppressed this surge in TST and significantly attenuated the fall in core temperature. Similar results were observed following the systemic administration of ST-91, another alpha 2-adrenergic agonist which does not cross the blood-brain barrier. Central administration of ST-91 (50 micrograms/5 microliters, icv) was also successful in attenuating these temperature changes in the morphine-dependent rat. Adrenalectomy and peripheral administration of propranolol (10 mg/kg sc) both resulted in a significant attenuation of the surge in TST and the fall in core temperature in the morphine-dependent rat which suggest some peripherally mediated event is necessary to produce the full skin temperature surge. Collectively, the data suggest a role for the adrenal gland and adrenergic receptors in producing the surge in TST in morphine-dependent rats. It also suggests that the blocking effects of the alpha 2-adrenergic agonist can be mediated both centrally and peripherally.

Trans-cranial electrical stimulation attenuates abrupt morphine withdrawal in rats assayed by remote computerized quantification of multiple motor behavior indices

The goal of the present study was to assess the effects of trans-cranial electrical stimulation on the behavioral signs of the abrupt withdrawal syndrome of rats. However, this goal also necessitated the introduction of an experimental model measuring animal behavior for prolonged periods of time using a computerized animal activity monitoring system to quantify spontaneous motor activities associated with abstinence behavior. Comparable withdrawal severity was obtained by both the activity monitoring system and investigator observation of motor signs of abstinence behavior. Moreover, using this system we demonstrate a time-dependent effect of electrical stimulation in reducing the severity of various indicies of motor hyperactivity associated with abrupt morphine withdrawal in rats.

Context-specific morphine withdrawal in rats: Duration and effects of clonidine.

Rats previously injected with morphine in a particular environment (paired rats) emitted more withdrawal symptoms in that environment than did rats previously injected with morphine in another environment (unpaired rats) after both 1 day and 5 days of morphine abstinence. Thus, reexposure to an environment previously associated with morphine can elicit context-specific withdrawal even after several days of morphine abstinence. Clonidine (0.06 mg/kg) reduced most of the withdrawal symptoms seen 5 days after morphine abstinence in both the paired and unpaired rats. However, clonidine enhanced many of the withdrawal symptoms in both groups of rats during naltrexone-precipitated withdrawal 1 day after morphine abstinence.

Context-specific morphine withdrawal in rats: Duration and effects of clonidine.

Context-specific morphine withdrawal in rats: Duration and effects of clonidine.

Clonidine attenuates increased brain glucose metabolism during naloxone-precipitated morphine withdrawal

The effect of two doses of clonidine on regional cerebral metabolic rates for glucose were measured during morphine withdrawal in rats. In the first study, 0 or 200μg/kg clonidine was administered to rats subjected to naloxone-precipitated morphine withdrawal (naloxone, 0.5 mg/kg, s.c.), and to non-dependent control rats. In a second study of similar design, 0 or 20μg/kg clonidine were administered. Withdrawal signs in rats subjected to naloxone-precipitated morphine withdrawal and receiving 0, 20 or 200 μg/kg clonidine were also assessed. Naloxone-precipitated morphine withdrawal stimulated regional cerebral metabolic rates for glucose (59 of 83 regions in study no. 1; 73 of 83 regions in study no. 2). At 200μg/kg, clonidine attenuated this effect (33 of 59 regions). Although 200μg/kg clonidine directly suppressed regional cerebral metabolic rates for glucose in many regions (significant main effect of clonidine), it attenuated the naloxone-precipitated morphine withdrawal effect specifically in the lateral septal nucleus, medial habenula, subiculum and gracile nucleus (significant interactions between clonidine and morphine withdrawal). The 20μg/kg dose of clonidine had no statistically significant effect. In behavioral experiments, both doses of clonidine diminished withdrawal in that there was no diarrhea, fewer wet-dog shakes and less abnormal posturing. However, locomotion, grooming and jumping were increased by clonidine. Most of these effects were statistically significant only with the 200μg/kg dose. The results of these studies show that clonidine reduces morphine withdrawal-induced increases in regional cerebral metabolic rates for glucose in many brain regions, irrespective of the distribution ofα 2-adrenoceptors. Although clonidine has been thought to ameliorate morphine withdrawal by actions primarily at the locus coeruleus and central amygdala, it may play a major role in other regions as well.

Trans-cranial electrical stimulation attenuates the severity of naloxone-precipitated morphine withdrawal in rats

The expression of morphine withdrawal in rats has been demonstrated as dependent upon the integrity of specific brain regions. Focal intracranial electrical stimulation of some of these sites results in the attenuation of withdrawal severity. The present study demonstrates that electrical auricular stimulation, in a paradigm known to attenuate nociceptive responses of several brain nuclei, attenuates the severity of naloxone-precipitated morphine withdrawal in rats. This simple non-invasive treatment, based on long-standing principles of electroacupuncture, may provide a useful adjunct for therapy of the narcotic withdrawal syndrome.

Modification of morphine withdrawal in rats by alterations of the endogenous opioid system: Effects of actinonin and GEMSA

AbstractThe results show that actinonin (50‐200 m̈g, i.c.v.), an inhibitor of the three enzymes involved in the biodergradation of enkephalins, attenuates, while guanidinoethylmercaptosuccinic acid (GEMSA 3‐12 m̈g, i.c.v.), an inhibitor of enkephalin‐synthesising carboxypeptidase, aggravates some naloxone‐precipitated withdrawal signs in chronic morphine‐dependent rats. The results suggest that alterations in the functional activity of the endogenous opioid system by drugs that affect enkephalin metabolism might have a significant effect on the severity of opiate withdrawal.

Changes in locomotor-activity patterns as a measure of spontaneous morphine withdrawal: no effect of clonidine

The anti-withdrawal action of clonidine was studied in a model of spontaneous morphine withdrawal in rats. After withdrawal the behaviour of the animals was registered continuously for several days. In the initial phase of induction of dependence the locomotor activity was enhanced during daytime. Partial tolerance to this increase developed in the course of 3 weeks. In morphine-withdrawn animals the activity decreased strongly at night, and this effect was maximal on the second night after removal of morphine. After four nights the nightly activity was restored. Treatment with clonidine (100 μg/kg s.c. twice daily) changed neither the observed decrease in nightly locomotor activity nor other withdrawal symptoms such as a decrease in food intake and loss of body weight. In non-dependent animals clonidine induced a biphasic effect in locomotor activity, i.e. a decrease in the first few hours of the night and an increase in the second part of the night. The latter can be interpreted as a rebound phenomenon occuring after only three injections. It was concluded that clonidine was not effective as an anti-withdrawal compound in a model for spontaneous morphine abstinence. The low incidence of symptoms relating to a hyperactive sympathetic system during spontaneous withdrawal may be an explanation for the absence of an effect of clonidine.

Cyclosporine and alpha-interferon do not attenuate morphine withdrawal in rats but do impair thermoregulation

Immunomodulating drugs as diverse as alpha-interferon and cyclosporine have been reported to attenuate physical signs of morphine withdrawal in rats. On the basis of these results, the immune system has been claimed to be involved in opiate addiction. To assess whether this is the case, the effects ofalpha-interferon and cyclosporine were studied on objective signs of morphine withdrawal in morphine-dependent rats. Rats made dependent upon morphine by implantation of a 75-mg morphine pellet were challenged three days later by naloxone (1 mg/kg). Pretreatment with alpha-interferon (150 U/g) or cyclosporine (15 mg/kg) did not attenuate the reduction in body weight or the behavioral suppression induced by naloxone in morphine-dependent rats trained to press a lever for food reinforcement on a fixed-ratio 10 schedule. Alpha-interferon pretreatment blocked the capacity of naloxone to decrease body temperature in these rats and actually induced an hyperthermic response. In contrast, cyclosporine tended to enhance the drop in body temperature induced by naloxone. This last effect was more striking when the rats were placed in a cold room at 3.5°C. Cyclosporine by itself induced a drop in body temperature in normal rats exposed to 3.5°C. These results indicate that alpha-interferon and cyclosporine impair thermoregulation but do not directly interfere with morphine withdrawal signs.

Ketanserin and pirenperone attenuate acute morphine withdrawal in rats

The involvement of serotonin 2 (5-HT 2) receptors in the expression opiate withdrawal was examined using a behavioral test for acute morphine dependence. The 5-HT 2 antagonists, ketanserin and pirenperone, injected shortly before naloxone, attenuated the naloxone-induced suppression of an autoshaped lever-touch response in rats treated 4 h earlier with a moderate dose of morphine. A low dose of pirenperone was also effective in blocking withdrawal-induced hypothermia. These data support the hypothesis that 5-HT is involved in the expression of opiate withdrawal-induced hypothermia. These data support the hypothesis that 5-HT is involved in the expression of opiate withrawal.

Supraspinal and spinal mediation of naloxone-induced morphine withdrawal in rats

Unanesthetized rats, made physically dependent over 5 days by chronic intra-arterial infusion of increasing concentrations of morphine (35–100 mg/kg/day) underwent withdrawal by naloxone (6 μg) injection into either the lateral ventricle (i.c.v.), fourth ventricle (V4), intrathecal subarachnoid space (i.t.), or intra-arterially (i.a.) and were evaluated for cardiovascular and behavioral signs of precipitated abstinence. Naloxone i.c.v. produced a significantly greater increase in the magnitude and duration of withdrawal hypertension than did V4 injection. Naloxone i.t. produced a distinctively different, persistent, pressor response as compared to i.c.v., V4 or i.a. routes of administration, although no quantitative differences in behavioral signs of withdrawal were observed. Morphine-dependent, spinal transected (C1) animals generated an augmented pressor response to i.c.v. or i.t. naloxone. This pressor response was accompanied by a significant reduction in core temperature (0.50–0.79 °C). Both the naloxone-induced pressor and hypothermic responses were abolished by ganglionic (hexamethonium, 100 mg/kg, i.a.) or peripheral α-adrenergic (phentolamine 4 mg/kg, i.a.) blockade. The hypertensive and hypothermic effects of naloxone also were prevented in transected dependent rats by prior spinal pithing. We conclude that in morphine-dependent rats: (1) supraspinal sites rostral to the V4 mediate a more intense naloxone-induced pressor response than caudal regions; (2) cardiovascular and behavioral signs of withdrawal can be precipitated via the spinal cord of intact animals; and (3) the production of withdrawal hypertension and hypothermia in spinal transected morphine-dependent rats indicates that these abstinence signs can be mediated through neuronal pathways within the spinal cord.