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PubMedDate not supplied

The effect of aspartic acid on the intensity of physical dependence in morphine dependent mice.

The mice (Balb/C strain) given 2% aspartic acid in 5% saccharose solution or only saccharose solution (p. os) starting 12 hr before the sc morphine pellet implantation until the removal of pellet were rendered physically morphine dependent. During the development of morphine dependence and after the removal of pellets (on 3-d day) spontaneous motor activity and analgesic threshold were measured as reliable abrupt withdrawal signs. Aspartic acid prevented to some extent the appearance of symptoms of physical morphine dependence.

Analgesia↗
PubMed1977

The effects of ethanol and pentobarbital on the naloxone precipitated escape response in morphine dependent mice.

Morphine dependence in mice is produced in a two day test. The effects of (1) ethanol, (2) pyrazole, (3) ethanol with pyrazole, and (4) pentobarbital are observed and recorded on the naloxone precipitated escape response in morphine dependent mice. Ethanol suppresses the escape response in doses of 2.0 and 3.0 g/kg which produce mean blood ethanol concentrations of 1.88 and 3.28 mg/ml, respectively. When a pyrazole regimen is employed with morphine dependent mice, ethanol reduces or abolishes the naloxone precipitated escape response at doses of 1.0, 2.0 and 3.0 mg/kg. The corresponding mean blood ethanol concentrations are 1.14, 2,82 and 3.74 mg/ml, respectively. When pentobarbital (20 and 30 mg/kg) is given to morphine dependent mice, jumping bevarior is prevented following naloxone injection. Since narcotic antagonists such as naloxone may be employed in studying the phenomenon of physical dependence on ethanol based on the hypothesis of a relationship between endogenous opiates and ethanol dependence, it is essential to verify that blood ethanol concentrations are low enough so that ethanol will not interfere with the effects of naloxone in ethanol dependent animals.

Animals↗
PubMed1975

Urinary excretion of morphine and its metabolites in morphine-dependent subjects.

Morphine, morphine glucuronide, morphine ethereal sulfate, normorphine and total normorphine in three consecutive 24-hour urines of four morphine-dependent subjects receiving morphine sulfate 60 mg s.c. q.i.d. have been determined with thin-layer chromatography and gas-liquid chromatography. With thin-layer chromatography the mean daily excretion of free morphine was 10% of the administered dose; morphine glucuronide, 65%; total (free and acid hydrolyzable conjugate) morphine 85%; and total normorphine, 3.5%. With gas-liquid chromatography, the percentage excretion for free morphine was 10%; total morphine, 74%; free normorphine, 1%; and total normorphine, 4%. The excretion of total drug was linearly related to the volume of the daily urine output.

Adult↗
PubMed1979

Mode of antagonistic action of levallorphan in morphine-dependent rats and assessment of physical dependence liability.

The antagonistic mode of levallorphan in rats dependent on morphine or codeine was studied from the viewpoints of the doses of morphine and the lengths of administration and also from the standpoint of timing of the challenge. In morphine-dependent rats on morphine-admixed food (60--100 mg/kg/day) for 1, 3 and 6 weeks, the rate of maximum weight loss on application of levallorphan (2 mg/kg, s.c.) did not correlate with the length of morphine treatment. The rate of weight loss on single application of levallorphan 0, 6, 12 or 24 hours after withdrawal or morphine was lower with the passage of time after the withdrawal. Rats which were given levallorphan 3 times in succession, i.e., at 0, 5 and 10 hours after morphine withdrawal showed such a pattern of weight loss that the first application of levallorphan resulted in 7% loss, while with the second and third applications there was little weight loss. Despite the continued withdrawal, the animals began to gain body weight as early as 14 hour, and body weight was totally recovered before the withdrawal in 24 hour. In conclusion, it is advisable to challenge with levallorphan at 0 hour of withdrawal to obtain qualitative and reproducible results. In addition, the application of levallorphan to morphine-dependent rats at adequate intervals provides for the early recovery of abstinence signs.

Animals↗
PubMed1976

Dopaminergic-cholinergic interactions in naloxone-induced circling in morphine-dependent rats with nigral lesions.

3-4 weeks after placement of a unilateral, electrolytic lesion of the substantia nigra zona compacta, rats were highly dependent on morphine by the s.c. morphine pellet implantation technique. Following challenge with a supramaximal naloxone dose of 20 mg/kg i.p., both continuous contralateral circling behavior and severe withdrawal signs in morphine-dependent, lesioned rats were elicited. After various drug pretreatments, the contralaeral circling behavior precipitated by naloxone was: (a) reversed to ipsilateral circling by i.p. apomorphine or d-amphetamine, (b) unaltered by i.p. haloperidol or intraneostriatal arecoline administered into the intact neostriatum, and (c) reversed to ipsilateral circling by the administration of atropine into the intact neostriatum. Atropine, apomorphine and amphetamine all interfered with the manifestation of naloxone-precipitated abstinence. These data suggest that a diminution of dopaminergic or an enhancement of cholinergic activities, or both, occur at the level of the neostriatum during naloxone-precipitated withdrawal in morphine-dependent rats.

Animals↗
PubMed1975

[Morphine dependence and preference. (I). Morphine preference in naive and morphine-experienced rats].

The spontnaeous morphine intake ratio (M-SIR) under free access to morphine-admixed food and quinine-admixed food conditions was measured for 3 weeks in naive and morphine-experienced rats. In the case of morphine (0.5 mg/g of food) vs. quinine (0.5 mg/g of food), naive rats gradually increased M-SIR from 17% to 77%. Using a higher level of morphine- and quinine-admixed food (1 mg/g vs. 1 mg/g of food), M-SIR was more rapidly increased than that in the lower group. Thus while on the 10 approximately 60 mg/kg/day dose range, the M-SIR was gradually increased dose dependently in naive rats due mainly to the positive reinforcing properties of morphine. Morphine-experienced rats showed a significant increase in M-SIR for the first 4 days specifically as compared with naive rats. Morphine dependent rats thus obtained morphine in sufficient amounts to maintain dependent states only after the first 2 approximately 3 days. This choice behavior revealed the psychological aspects of morphine dependence in rats and the preference for morphine was also observed after withdrawal for more than 2 weeks as secondary abstinence syndrome.

Animals↗
PubMed1979

[Hypothalamo-pituitary-adrenocortical (HPA) function in the morphine dependent rat (author's transl)].

Morphine dependence was induced by ten daily administrations of morphine with gradually increasing dosage (40--160 mg/kg/day s.c.) to male Sprague-Dawley rats, the dosage being divided in 2/day for the first 8 days and 4/day for the last 2 days. Diurnal variation in body weight in morphine dependent rats was the same as in naive rats. Although body temperature in the naive rats showed a diurnal variation with the highest at 3:00 and the lowest at 15:00, in the morphine dependent rats there was no distinct variation. Plasma corticosterone level (PC) in naive rats showed diurnal variation with the peak at 21:00 and the trough at 9:00. PC in morphine dependent rats showed the same diurnal variation as did the naive rats, while such disappeared following pentobarbital anesthesia (80 mg/kg i.p. for 45 min) and PC was low all during the day. The PC increase following formalin administration to morphine dependent rats was higher than in naive rats. 0.1 mg/kg s.c. of dexamethasone completely inhibited PC increase after formalin in naive rats, but the dexamethasone inhibition in morphine dependent rats was not complete even with a larger dose, i.e. 10 mg/kg s.c. Diurnal variations and other differences were not detected in the adrenal response to ACTH (in vivo, in vitro) between naive and morphine dpendent rats. These results suggest that HPA function takes part in the development of morphine dependence.

Adrenocorticotropic Hormone↗
PubMed1979

Discriminative stimulus effects of naltrexone in the morphine-dependent rat.

Rats maintained physically dependent upon morphine by scheduled access to drinking water containing morphine were trained to discriminate between s.c. injections of saline and 0.1 mg/kg of naltrexone in a discrete trial avoidance procedure in which a response on one of two choice levers would prevent or terminate the delivery of mild electric shocks to the floor of the test chember. Stimulus control of behavior by naltrexone in the morphine-dependent rat (defined as the reliable completion of at least 18 trials of a 20-trial session on the appropriate choice lever) had many of the features previously described for the stimulus control of behavior by morphine in the nondependent rat: long-term stability and reproducibility, orderly dose- and time-effect relationships and pharmacologic specificity. Stimulus control by naltrexone was blocked in a dose-related manner by morphine, an effect completely surmounted by a 10-fold increase in the dose of naltrexone suggesting a competitive antagonism. The naltrexone-induced discriminative stimuli appeared to be related to precipitated morphine withdrawal phenomena: following the abrupt withdrawal of morphine the amount and time course of naltrexone-appropriate responding were directly related to the degree of physical dependence; loss of body weight, a reliable index of morphine withdrawal in the rat, paralleled changes in naltrexone-appropriate responding; the maximum level of naltrexone-appropriate responding produced by a total of eight narcotic antagonists with agonist activity of differing prominence was a function of the extent of separation of the agonist and antagonist components of action of the drugs. Control of behavior by stimuli associated with morphine withdrawal may afford a specific animal model for studying factors relevant to the perpetuation of chronic drug use by human addicts.

Animals↗
PubMed1978

Tolerance, dependence and lethality in morphine-dependent mice after repeated oral administration of methadone.

Mice were rendered tolerant to and dependent on morphine via a morphine pellet implantation. Three days later methadone hydrochloride was administered at a dose of 100mg/kg per os 3 hours after pellet removal and then daily for a total of 5--6 days. This dose of methadone was shown to exhibit a high efficacy for the blockade of morphine abrupt withdrawal jumping and only minimal toxicity. Under these conditions, the level of analgetic tolerance with respect to morphine and methadone and the level of dependence as measured by the naloxone ED50 were initially elevated by the morphine treatment. However, upon substitution with oral methadone these levels declined with time at a rate which did not differ from that of a group of mice receiving only water after morphine pellet removal. Despite these findings, the methadone treatment was associated with an increasing tolerance to methadone lethality during the administration of this narcotic which was nearly double that of a similarly treated water control group by the sixth day. This observation could not be explained by an elevation in the level of cellular tolerance rendered by the methadone treatment since the morphine LD50 was not elevated following identical treatment with morphine and then methadone. The significance of these results is discussed with respect to the role of methadone administration and its metabolism in the modification of tolerance and dependence.

Administration, Oral↗
PubMed1976

Effects of morphine and naloxone on Renshaw cells and spinal interneurones in morphine dependent and non-dependent rats.

The effects of microelectrophoretically administered morphine, naloxone, levorphanol and dextrorphan have been investigated on Renshaw cells and interneurones in the spinal cord of morphine-dependent and non-dependent anaesthetized rats. Morphine excited cholinoceptive neurones and enhanced the excitatory actins of acetylcholine and L-glutamate. This action of morphine appeared to be stereospecific and was antagonized by naloxone. Naloxone also antagonized acetylcholine-induced excitation but not L-glutamate-induced excitation. In dependent rats morphine was a more effective excitant of cholinoceptive neurones and naloxone was more effective as an antagonist of acetylcholine-induced excitations. These observations were interpreted as indicating that cholinergic mechanisms may be involved in morphine dependence and naloxone-precipitated abstinence.

Acetylcholine↗
PubMed1976

Changes in sensitivity to apomorphine during morphine dependence and withdrawal in rats.

Stereotyped behavior induced by injection of apomorphine hydrochloride (10 mg/kg i.p) was measured in control rats, rats made dependent on morphine and dependent rats undergoing naloxone-precipitated withdrawal. The dose of apomorphine chosen was approximately the ED50 dose, so that changes in sensitivity to apomorphine in either direction could be determined. Rats which had received a subcutaneous morphine (75 mg) pellet implant 72 hours previously demonstrated an increased sensitivity to apomorphine when compared with placebo-implanted controls. During withdrawal precipitated by injection of naloxone hydrochloride (0.2 mg/kg i.p.) this increased sensitivity disappeared. Naloxone alone, in a dose of 1.0 mg/kg but not 0.2 mg/kg, significantly antagonized apomorphine-induced stereotyped behavior and these effects of apomorphine were also reduced by an acute injection of morphine sulfate (10 mg/kg). The significance of these findings with regard to changes in central dopaminergic systems during dependence and withdrawal is discussed.

Animals↗
PubMed1976

Inhibition of naloxone-induced withdrawal in morphine dependent mice by 1-trans-delta9-tetrahydrocannabinol.

The effects of various doses of 1-trans-delta9-tetrahydrocannabinol (delta9-THC) on naloxone-induced withdrawal were studied in mice rendered dependent on morphine by the pellet implantation procedure. When administered i.p., 30 min prior to naloxone, delta9-THC, inhibited the naloxone-induced withdrawal jumping response. Two other signs of morphine withdrawal (defecation and rearing behavior) were also suppressed by deltapTHC. It is suggested that delta9-THC or some of its derivatives may have potential use in narcotic detoxification.

Animals↗
PubMed1977

Dopaminergic mechanisms in precipitated withdrawal in morphine-dependent rats.

Rats were made dependent on morphine by implantation of a pellet and withdrawal was precipitated by the injection of naloxone 72 hours later. Withdrawal was assessed by scoring each of the following signs individually: chewing, licking, teeth chattering, facial tremor, grooming, writhing, diarrhea, weight loss, wet dog shakes, head shakes and hypothermia. The role of dopamine in withdrawal was determined by pretreating the animals with apomorphine or pimozide. Apomorphine in the lower dose range (0.625-1.25 mg/kg) produced a significant decrease in teeth chattering, writhing, weight loss and wet dog shakes. The high dose of apomorphine (2.5 mg/kg) significantly inhibited all features of the withdrawal except writhing and weight loss. Pimozide caused a significant increase in chewing, writhing and head shakes, but only with the highest dose used (0.5 mg/kg). Pimozide (0.5 mg/kg) significantly reduced withdrawal hypothermia, but apomorphine had no effect on this sign except at the highest dose when withdrawal hypothermia was increased.

Animals↗
PubMed1976

The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog.

Three different syndromes produced by congeners of morphine have been identified in the nondependent chronic spinal dog. These syndromes have been attributed to interaction of agonists with three distinguishable receptors (mu, kappa and sigma). Morphine is the prototype agonist for the mu receptor, ketocyclazocine for the kappa receptor and SKF-10,047 for the sigma receptor. The morphine syndrome (mu) in the dog is characterized by miosis, bradycardia, hypothermia, a general depression of the nociceptive responses and indifference to environmental stimuli. Ketocyclazocine (kappa) constricts pupils, depresses the flexor reflex and produces sedation but does not markedly alter pulse rate or the skin twitch reflex. SKF-10,047 (sigma), in contrast to morphine and ketocyclazocine, causes mydriasis, tachypnea, tachycardia and mania. The effects of these three drugs can be antagonized by the pure antagonist naltrexone, indicating that they are agonists. Further, chronic administration of morphine, ketocyclazocine and SKF-10,047 induces tolerance to their agonistic effects. Morphine suppresses abstinence in morphine-dependent dogs while ketocyclazocine does not. Ketocyclazocine at best precipitated only a liminal abstinence syndrome in the morphine-dependent dog, indicating that it had little affinity for the morphine receptor. Ketocyclazocine thus appears to be a selective agonist at the kappa receptor. Further, it has been shown that buprenorphine is a partial agonist of the mu type which both suppressed and precipitated abstinence in the morphine-dependent dog while morphine and propoxyphene are stronger agonists. Apomorphine and SKF-10,047 produce similar pharmacologic effects suggesting that sigma activity may involve a dopaminergic mechanism.

Animals↗
PubMedDate not supplied

Conditioned behavioral and physiological changes associated with injections of a narcotic antagonist in morphine-dependent monkeys.

Environmental stimuli which are repeatedly associated with the nalorphine-induced withdrawal syndrome in morphine-dependent monkeys acquire the ability to produce a variety of conditioned behavioral and physiological responses. Morphine-dependent rhesus monkeys were studied under a fixed-ratio schedule where every tenth lever press produced a food pellet. After several pairings of a stimulus (light or tone) with intravenous injection of a dose of nalorphine which produced an immediate and severe withdrawal syndrome, onset of the stimulus alone produced conditioned suppression of lever pressing heart-rate decrease, vomiting and salivation. Conditioned suppression of responding and conditioned heart-rate changes persisted in post-dependent monkeys for one to four months after termination of chronic morphine treatment. No conditioned electrocardiogram, respiration or temperature changes were ever seen. A second group of morphine-dependent rhesus monkeys was studied under a schedule where every lever press produced an intravenous injection of morphine. After 10 pairings of a light with the intravenous injection of a dose of nalorphine which produced marked withdrawal signs and increased responding for morphine, presentation of the light and injection of saline produced conditioned increases in responding for morphine. A third group of morphine-dependent rhesus monkeys was studied under a schedule where every nth lever press (n=1 to 10) terminated a stimulus light associated with periodic injections of nalorphine or naloxone; lever-press responding was engendered and subsequently maintained. Thus, stimuli associated with the nalorphine-- or naloxone--induced withdrawal syndrome can either suppress, enhance or maintain behavior depending on the schedule conditions.

Animals↗
PubMed1976

The effects of morphine and nalorphine-like drugs in the nondependent, morphine-dependent and cyclazocine-dependent chronic spinal dog.

A series of morphine-like and nalorphine-like drugs were studied in the nondependent, morphine-dependent and cyclazocine-dependent chronic spinal dog. In the nondependent dog, three profiles of activity were found which could be utilized to distinguish between morphine, WIN 35, 197-2 and cyclazocine. Propiram, a prototypic partial agonist of the morphine type, produced morphine-like effects in nondependent dogs and both precipitated and suppressed abstinence in cyclazocine-dependent dogs as was needed to precipitate abstinence in morphine-dependent dogs. WIN 35, 197-2, a strong agonist in the guinea-pig ileum which has been shown to be resistant to antagonism by naloxone, neither precipitated nor suppressed morphine abstinence but suppressed cyclazocine abstinence. In the nondependent dog, it depressed the flexor reflex but not skin twitch reflex. Cyclazocine altered reflex activity much like WIN 35, 197-2 but produced tachycardia, tachypnea, mydriasis and canine delirum. The morphine and cyclazocine precipitated and withdrawal abstinence syndromes were qualitatively different. Twenty times as much naltrexone was needed to precipitate abstinence in morphine-dependent dogs. Nalorphine both precipitated and suppressed cyclazocine abstinence and appeared to be a partial agonist of the nalorphine-type. Morphine suppressed the cyclazocine abstinence syndrome. Cross-tolerance was not observed in ketocyclazocine-dependent dogs. These data are consistent with the hypothesis that there are strong and partial agonists of the mu and kappa types, and further, that physical dependence on morphine and cyclazocine is mediated through different receptors. WIN 35, 197-2 appears to be a pure strong agonist of the kappa type. Cyclazocine is a mu antagonist and mixed kappa and sigma agonist.

Animals↗
PubMed1976

Precipitation of abstinence-like syndrome in morphine-dependent mice by pargyline.

In mice rendered morphine-dependent by pellet implantation for 3 days, the administration of pargyline 6 hours after pellet removal intensified narcotic abstinence behavior, particularly the narcotic withdrawal jumping response. Pargyline, 75 mg/kg i.p., caused a 6- to 9-fold increase in the incidence of jumping in mice withdrawing from morphine 6 hours after removal of the pellet, whereas this effect was not observed: 1) 1 hour after the injection of pargyline or 2) in animals still implanted with the morphine pellet. The median effective dose (ED50) of pargyline required to elicit withdrawal jumping in mice implanted with morphine decreased with increasing physical dependence. The ED50 for 72 hours was about one-sixth that after 24 hours of implantation. Additionally, pargyline potentiated naloxone-precipitated withdrawal jumping as evidenced by a reduction of the naloxone ED50 by approximately one-half. Administration of other monoamine oxidase inhibitors such as pheniprazine, iproiazid or tranylcypromine failed to alter the indicence of jumping in dependent mice undergoind abrupt morphine with drawal. Further, dopamine receptor stimulation by amphetamine, pheniprazine or amantadine antagonized the pargyline-induced jumping response. These data suggest that the increased incidence of withdrawal jumping observed after pargyline in morphine-dependent mice is not related to monoamine oxidase inhibition but rather to a possible pargyline-induced decrease in dopaminergic activity.

Amantadine↗