Morphine analgesia in grouped and isolated rats

The effects of long-term isolation of young adult male rats on the analgesic effects of morphine were investigated. Isolated rats developed altered patterns of behavior, including muricidal behavior in some animals. Analgesic activity of morphine was assessed with both the tail compression and the hot plate methods. The results indicate that chronically isolated rats, whether developing muricidal behavior or not, show no alteration in either pain thresholds or in their response to morphine-induced analgesia.Supported in part by NATO Research Grant No. 719 and USPHS Grant DA 00376.Visiting Scientist from the Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pa., U.S.A.     

Effect of valproic acid on brain serotonin metabolism in isolated and grouped rats

The effect of the GABA transaminase inhibitor valproic acid (DPA) on serotonin (5HT) metabolism of different brain regions were studied in both grouped and isolated rats. One hour after DPA injection 5HT levels in the amygdala were increased in grouped and isolated rats. In the hypothalamus of grouped rats, changes in 5HT metabolism were also found. The alteration in 5HT metabolism in grouped rats was reversed 150 min after injection of DPA. At this same time, a large and significant increase in 5HT turnover was observed in all brain areas examined in isolated rats. It can be concluded that prolonged isolation induces a differential sensitivity to the effects of DPA leading to differences in 5HT metabolism: the drug effect being more intense in isolated rats.     

Morphine ingestion: Genetic control in mice

C57BL/6J mice will drink large amounts of, and display a highly positive preference for, morphine sulfate when it is dissolved in an aqueous solution of sodium saccharin. In identical test situations DBA/2J mice will drink very little of, and display a strong avoidance toward, the morphine-saccharin solution. This clear separation between morphine-accepting and morphine-rejecting animals within a single species combined with a quick and simple method of inducing high levels of morphine ingestion could facilitate the discovery of causal factors in opiate addiction.     

Morphine induces delayed anorexia in rats

The delayed suppression of feeding caused by morphine was investigated in the rat. A single injection of morphine evoked a triphasic influence on feeding: a brief (1 h) severe anorexia was followed by hyperphagia (3 h) and a mild (20%) yet persistent (4–24h) anorexia. This latter anorexic effect was at least partially naltrexone reversible, and the duration of this antagonism (8 h) was longer than that of naltrexone's anorexic effect (4 h). Delayed morphine anorexia cannot be ascribed to morphine's initial stuporific influence, and it was not dependent upon previous feeding or deprivation. It was not due to gastric distension. The specificity and significance of this anorexia is discussed.     

Morphine reduces social cohesion in rats

The effect of low (1 mg/kg) doses of morphine on maintenance of physical proximity were evaluated in paired rats observed in a 4 square foot test arena. Morphine reliably reduced proximity maintenance time, and this was apparently not due to sedation, since the effect was unmodified by doses of amphetamine which substantially increased motor activity. The effects of naloxone were inconsistent on this measure of social motivation. In general, the results are consistent with the theoretical proposition that a brain neurochemical change which might lead to social attraction is the activation of endogenous opioid systems. When opiate activity is exogenously sustained, animals exhibit a subnormal tendency to be gregarious.     

The “isolation syndrome” in mice

Isolation has been widely described to induce a strong aggressive behavior in many animal species and expecially in rodents.However, a deeper analysis of such altered behavior induced by isolation, allows the identification, at least in mice, of several other changes involving numerous peripheral, behavioral and neurochemical functions, in such a way to debouch into a complex symptomatology. As a consequence of the manifold aspects involved in this experimental situation, the definition isolation syndrome seems to be much more adequate than the simplest definition of aggressiveness by isolation. On this frame work, some similarities with psychoneurosis in men are also suggested.     

Haloperidol catalepsy in grouped and isolated mice.

A method was worked out to assess in a quantitative and dose-dependent way the development of catalepsy of mice after low doses of haloperidol. This method was also capable of detecting the anticataleptic effect of phenytoin and the catalepsy-enhancing effect of nikethamide. After 4 weeks' isolation, the mice became aggressive and revealed increased susceptibility to the cataleptic effect of haloperidol. The analysis of the data indicates that in these experiments altered central mechanisms were more important than changes of the peripheral pharmacokinetics of haloperidol.     

Morphine dependence in rats: Secondary reinforcement from environmental stimuli

Rats which were physically dependent on morphine were repeatedly placed in distinctive environments immediately after being injected with their daily dose of the drug (120 mg/kg). The effects of morphine, e.g. reduction of withdrawal symptoms, were thus associated with particular environmental stimuli and when the rats were tested in withdrawal, they preferred these environments to unfamiliar neutral ones. They also tended to have higher photocell activity scores during these tests. Avoidance of such environments was not shown by rats which had repeatedly been placed in them when in states of withdrawal.     

Effects of N-(ethyl-2 pyrrolidinyl-methyl)-2-methoxy-5-sulfamoil-benzamide (sulpyrid) on the central nervous system in rats and mice

Sulpyrid is a new psychoactive drug and several clinical studies indicate a series of polymorphic therapeutic indications.Experimentally, sulpyrid blocks muricide reactions by isolation in rats but it is not active on aggressiveness in mice. Sulpyrid also modifies the exploratory activity in mice in which it decreases the brain 5-hydroxytryptamine turnover, as well as in rats.     

Morphine preference in individual rats after morphine ingestion

Individual differences in drug intake were investigated. Inbred Sprague-Dawley male rats were choice-tested after various periods of morphine ingestion. Nearly 10% of the rats showed more than 50% preference already after 4 days ingestion on 340 mg morphine/kg/day, while a further 10% had a mean preference less than 30% over 6 days of choice, even after as long as 38 days' treatment on this same dose. High morphine preference was stable for long choice periods. It was also found that a high morphine preference level in an individual rat persisted over several choice tests, even if the animals had been without morphine for several months. The ₂-agonist clonidine diminished high preference to the same extent as it diminished over-all morphine preference. There were no differences in food intake, body weight gain, severity of abstinence reactions, morphine serum levels, taste sensitivity tested with quinine, or learning the choice test behaviour comparing extremely high and low morphine preference rats. Thus, two subgroups of high and low morphine-ingesting rats were identified in the Sprague-Dawley strain.     

Morphine and self-stimulation: evidence for action on a common neural substrate

Recent studies have demonstrated that the self-stimulation phenomenon may provide a useful technique for investigating the rewarding properties of potentially addictive drugs such as morphine. The present study attempted to examine the nature of morphine's effects on self-stimulation by observing changes in rate-intensity functions following morphine administration. The results indicate that morphine markedly enhanced bar pressing for low intensity stimulation when the intensities were presented in an ascending sequence but morphine produced only slight changes in self-stimulation rates when a descending series was used. The failure of morphine to facilitate responding in the descending series suggests that adaptation of the self-stimulation system can block morphine's effects on this system. These findings appear to support the hypothesis that morphine affects the excitability of the neural system which mediates self-stimulation.     

Morphine,mescaline and cocaine on water maze discrimination in mice

Morphine, mescaline and cocaine have been tested in mice previously trained in a Y water, in two groups of parallel experiments. These involved, firstly (L Procedure), the consolidation of the innate tendency of the animals to direct towards the light, and secondly (D Procedure) the acquisition of a new behaviour, i.e. orientation toward the dark, opposite to the innate tendency.Both behaviour patterns were disrupted after the administration of morphine; following the administration of mescaline the reappearance of the innate tendency was evident, while innate behaviour was primarily affected by the administration of cocaine.     

Morphine and heroin effects on multiple fixed-interval schedule performance in rats

Five albino rats were trained to stability on a multiple fixed interval 60 sec-fixed interval 60 sec schedule in which one component ended with food pellet reinforcements and the other with saccharin solution reinforcements. Morphine sulfate in doses 3, 9, and 27 mg/kg i. p. and doses of heroin hydrochloride, 1, 3, and 9 mg/kg i. p., produced roughly comparable dose-related decreases in both rate of responding and index of curvature in both the food and saccharin components. A second experiment using 6 albino rats investigated the effects of repeated administration of equivalent doses of morphine sulfate (7.5 mg/kg) and heroin hydrochloride (3.0 mg/kg) on responding in the above multiple FI 60 sec-FI 60 sec schedule. Increases in rates of responding were noted following one or two injections. Drug effects on FI scalloping diminished after a few injections. The present studies report a morphine-heroin equivalency ratio consistent with that used to produce analgesia. No major behavioral differences were noted in the development of tolerance to the 2 drugs.     

Morphine dependence in rats produced after five days of ingestion

In the first experiment dose-dependent withdrawal signs following a nalorphine injection (either 2, 4, 8, 16, or 32 mg/kg, i.p.) were seen in rats that had been drinking sucrose morphine for 21 days. A non-dependent control group was generally unaffected by an injection of the antagonist (16 mg/kg, i.p.). In Experiment II, morphine withdrawal signs, both nalorphine induced and without nalorphine injection, were observed in rats which had been placed on only five days of morphine-adulterated food and sucrose morphine. Although both groups showed clear withdrawal signs after the drug was removed from their diet, the nalorphine-injected group showed more severe symptoms. By the eleventh day of withdrawal all rats had resumed normal eating and drinking and had nearly recovered their pre-drug body weights. It is concluded that reliable morphine dependence can be induced in five days, using a morphine-adulterated diet.This work was supported by NSF research grants B023365 and P2B0349 to K. A. Khavari.     

Morphine dependence in rats assessed in a shock discrimination task

The effects of chronic morphine sulfate (5 mg/kg/day for 14 days) on shock discrimination performance of rats were assessed in Experiment I. Significant tolerance developed to the disruptive effects of morphine on performance. A significant increase in discrimination performance was found 48h after the last injection in tests conducted without the injection environment cues present. Ten days after the chronic drug regimen, tests conducted 30 min after exposure to the injection-environment cues revealed no differences between animals previously administered morphine and control animals administered saline. In Experiment II, shock discrimination performance was assessed in a separate group of rats after exposure to a single injection of morphine sulfate (30 mg/kg), which eliminated associative processes, e.g., Pavlovian or instrumental conditioning, as factors in the subsequent behavioral tests for hyperalgesia. Significant changes in discrimination performance (primarily enhanced percent correct to the high shock stimulus) indicative of increased pain sensitivity were obtained in tests conducted 1,2, and 3, but not 9 days after the injection. These experiments indicate that increased pain sensitivity, as opposed to hyperresponsivity operationally measured in traditional analgesia tests (e.g., hot plate, jumpflinch, and tail flick), is a component of morphine withdrawal of a nonassociative origin.     

Effect of early and later colony housing on oral ingestion of morphine in rats

Male and female rats were raised from weaning either in isolation or in a large colony. At 65 days of age, halfe the rats in each environment were moved to the other. At 80 days, the animals were given continuous access to water and to a sequence of 7 solutions: 3 sweet or bitter-sweet control solutions and 4 different concentrations of morphine hydrochloride (MHCl) in 10% sucrose solution. Rats housed in the colony at the time of testing drank less MHCl solution than isolated rats, but no less of the control solutions. Colony-dwelling rats previously housed in isolation tended to drink more MHCl solution than those housed in the colony since weaning, but this effect reached statistical significance only at the lowest concentration of MHCl. These data were related to the hypothesis that colony rats avoid morphine because it interferes with complex, species-specific behavior.     

Morphine dependence in rats with medial forebrain bundle lesions

Rats with posterior medial forebrain bundle (PMFB) lesions and control rats were administered morphine chronically for 4 or 5 days via implanted subcutaneous silicone reservoirs. Following cessation of morphine administration after five days, PMFB rats showed less withdrawal-induced weight loss than control rats. Other PMFB and control rats were subjected to forced drinking of morphine solution for 9 days. PMFB rats consumed the morphine solution much more readliy than control rats, whereas intake of a quinine solution was similar in two other PMFB and control groups. These results suggest that the addictive and dependence properties of morphine may have separate mechanisms and based on previously reported neurochemical effects of PMFB lesions, that biogenic amines may be differentially involved in such mechanisms.This research was supported by NIMH grants MH 70082 and DA 00535 to S. D. Glick. The authors thank Stuart Greenstein for indispensable technical assistance.     

Dependence to morphine in differentially housed rats

Although the effects of differential housing, particularly isolation, on the action of several classes of pharmacological agents have been studied, little attention has been given to this factor in regard to narcotics. The present study involves the effects of long-term social isolation on dependence to morphine produced by pellet implants in rats. When abstinence was precipitated with naloxone, isolated rats demonstrated less jumping and less diarrhea than grouped rats. No differences were found in other signs. In addition, the differences were seen both in isolates developing muricidal behavior and those not developing this behavioral pattern.Supported in part by G. L. Pfeiffer Foundation, N.Y., NATO Research Grant No. 719, USPHS Grants DA 00049 and DA 00376.Visiting Scientist from the Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pa., U.S.A.     

Social behavioural profile of cocaine in isolated and grouped male mice

Studies concerning the relationship between cocaine and aggression in humans as well as in animals have discrepant outcomes. Increases, decreases, or no changes, have been reported after single or chronic cocaine administration in animal models. To clarify, at least in part, the complex behavioural actions of cocaine, the present study evaluated cocaine effects on social behaviours of mice exposed to different situations (isolated or group housed) using confrontations between two male mice in a neutral area. Different doses of cocaine (6, 25 and 50 mg/kg) were administered in a single or binge pattern (three doses in 24 h) and the behavioural test was performed 20 min after the last injection. No increases in aggression were observed in any situation tested. Instead, cocaine at the two higher doses employed (either in single or binge administration), decreased aggressive behaviours in isolated mice, with no changes being observed in grouped animals. In both types of animals, cocaine increased defensive elements (avoidance/flee) and abolishes social contacts. In conclusion, cocaine presents an anti-aggressive action and may be interpreted as having an anxiogenic-like effect.     

Morphine attenuates ultrasonic vocalization during agonistic encounters in adult male rats

Ultrasonic vocalizations (USV) in rats may communicate affective states during pain, sex and aggression. This proposal was evaluated in an experiment with adult male Long-Evans rats during agonistic encounters; specifically, morphine and naltrexone effects were studied on different types of USV by intruder rats exposed to resident attacks and to threat of attacks (i.e., intruder residing within the home cage of the resident but prevented from physical contact by a wire mesh cage). Intruders readily emitted USV during agonistic encounters. These calls consisted primarily of two distinct distributions of pure tone whistles: 0.3–3 s, 19–32 kHz (low) calls and 0.02–0.3 s, 32–64 kHz (high) calls. Sonographic analysis revealed a considerable repertoire of frequency modulated calls. Different types of vocalizations proved to be differentially sensitive to the opiate treatments: morphine (1–10 mg/kg SC) dose-dependently decreased the rate, duration and pitch of both low and high frequency USV during the threat of attack; this decrease in rate and duration measures was naltrexone-reversible (0.1 mg/kg IP). Interestingly, audible vocalizations were also emitted but were unaffected by morphine in this dose range. Concomitant with the decrease in USV after morphine was a dose-dependent decrease in rearing, walking and nasal contact behavior with increases in submissive crouch behavior and tail flick analgesia. The decreases in rate and duration of both low and high USV and the pitch of specific frequency modulated calls after morphine administration may reflect an attenuation of affective aspects of pain, and the many characteristics of US (rate, duration, pitch, frequency modulation, pre-and suffix attributes and temporal structure) point to potentially diverse functions. Morphine's pervasive effects on ultrasonic but not audible vocalizations, in addition to reflexive and submissive responses, provides evidence for opioid influences on affective as well as somatomotor responses to socially aversive situations.