Joseph Cochin

Effect of morphine sulfate on adenylate cyclase and phosphodiesterase activities in rat corpus striatum

Abstract The effect of morphine sulfate (MS) on adenylate cyclase (AC) and phosphodiesterase (PDE) activities in the rat striatum was investigated. MS produced a dose-dependent increase in basal AC activity and did not alter sodium fluoride-induced stimulation both in vivo (7.5–30 mg/kg, 1 hr pretreatment, i.p.) and in vitro (1–100μM). in vitro , when submaximal effective concentrations of dopamine and MS were combined, there was an additive effect. However, administration of MS in vivo did not alter dopamine-induced stimulation of AC activity. MS, in vitro and in vivo inhibited PDE activity in a dose-dependent manner only with the high substrate concentration (3.3 × 10 −3 M cyclic AMP). Preliminary results from this study indicate that morphine affects the cyclic AMP system.

Growth Retardation in Offspring of Female Rats Treated with Morphine Prior to Conception

Treatment of female rats with morphine sulfate for 5� or 10 days, prior to drug withdrawal for 5 days and subsequent mating, results in retarded growth of offspring. The effect is not present at birth but appears at 3 to 4 weeks of age. It occurs even though offspring are not exposed to morphine in utero or postnatally. It is not eliminated by cross-fostering and is apparently of prenatal origin

Tolerance to morphine in the rat: Its prevention by naloxone

Abstract Development of tolerance after a single injection of morphine in the Wistar-Lewis rat can be estimated by the attenuation of the response to a second injection of morphine given three days later. If naloxone is given 35 minutes after the first morphine injection and after the appearance of measurable analgesia, attenuation of the effects of the second morphine injection is not seen. It appears that naloxone blocks the development of tolerance to morphine even if given after the morphine-receptor interaction responsible for analgesia has been initiated. The temporal relationship between the prior injection of morphine and the subsequent administration of naloxone is being explored.

Changes in the striatal adenylate cyclase activity following acute and chronic morphine treatment and during withdrawal

an increase in striatal dopamine turnover (CLOUET & RATNER, 1970; COSTA et al., 1973; GAUCHY et al., 1973; GUNNE et al., 1969; PURI et al., 1973; SURGUE, 1973). The morphine-induced catalepsy was reversed after the administration of a dopamine agonist (KUSCHINSKY & HORNYKIEWICZ, 1972; PURI & LAL, 1973b). In addition, morphine also reversed apomorphine and amphetamineinduced stereotyped behavior (PURI et al., 1973). These studies suggested that morphine may interfere with dopaminergic neurotransmission. Continuous blockade of dopaminergic neurotransmission during chronic administration of morphine may cause supersensitivity of dopamine receptors. There are two lines of evidence to suggest that latent supersensitivity of dopaminergic receptors develop during morphine dependence. First, morphine-dependent rats have been reported to be more sensitive to the behavioral effects of those drugs that are known to stimulate dopamine receptors either directly or indirectly (GIANUTSOS et al., 1974; PURI & LAL, 1973a; PURI & LAL, 19736). Second, there is a marked enhancement of the effect of apomorphine, a direct-acting dopaminergic agonist (ANDEN et al., 1967; ERNST, 1967) on the striatal dopamine turnover in morphine-dependent rats (GIANUTSOS et al., 1974; PURI & LAL, 1973b; KUCHINSKY, 1975). Recently it has been suggested that dopamine receptors in the striatum are intimately associated with a dopaminesensitive adenylate cyclase and that the physiological effects of dopamine in the striatum may be mediated through cyclic AMP (IVERSEN, 1975). If this assumption is correct then dopamine-sensitive adenylate cyclase in the striatum can be utilized as a useful biochemical model to test systematically the effect of narcotic drugs on dopamine receptors. Since narcotic drugs affect the dopaminergic system, they may also influence the dopamine-sensitive cyclic AMP system. We therefore decided to investigate the effects of acute and chronic administration of morphine on dopamine-sensitive adenylate cyclase activity in the rat striatum. CHINSRY & HORNYKIEWICZ, 1972; PURI & LAL, 19736) and

Narcotic blockade, length of addiction and persistence of etonitazene consumption in rats.

Rats were given daily trials to determine relative preference for an opiate (etonitazene, ETZ) or for water. Animals with a greater history of previous drug exposure developed ETZ preferences more rapidly than did relatively drug-naive animals. Pretreatment with adequate blocking doses of naloxone reduced drug intake to near zero in most subjects. However, animals with the greatest history of prior addiction continued to drink large quantities of ETZ, despite pretreatment with relatively large doses of naloxone. These results can be explained by assuming that stimuli associated with the reinforcing properties of the opioid solution become strong conditioned reinforcers, capable of maintaining responding for long periods of time despite blockade of the reinforcement properties of the drug.

Narcotic blockade, length of addiction, and persistence of intravenous morphine self-administration in rats.

Four groups of rats differing in the number of periods of prior exposure to morphine sulphate in the i.v. self-administration paradigm were studied under conditions of narcotic blockade. Three groups of subjects also differing in the amount of prior exposure to morphine sulphate were studied under saline conditions. At effective blocking doses of naloxone, opioid-seeking behavior was eliminated in relatively drug naive animals, whereas the persistence of secondary reinforcers in rats with longer addiction histories served to maintain opioid consumption in the presence of adequate pharmacological blockade. Data from saline-treated animals were very similar to data obtained in naloxone-treated animals.The authors conclude that at adequate blocking doses of narcotic antagonist the length of addiction appears to be the best predictor of opioid consumption.

Morphine-based secondary reinforcement: effects of different doses of naloxone.

The effects of different doses of naloxone on morphine-based secondary reinforcement were studied in rats. On the first day a neutral stimulus (buzzer) was repeatedly paired with intravenous morphine infusions. Drug treatments consisted of Low, Medium, or High Naloxone doses, or No Naloxone. The next day the ability of the buzzer and saline infusion to support lever pressing was tested. High Naloxone blocked, and Low Naloxone partially blocked this morphine-based secondary reinforcement. Subjects in the Medium Naloxone group demonstrated an apparent avoidance of the lever, suggesting that the morphine infusions were aversive at this dosage level of naloxone. The secondary reinforcement tests reliably predicted behavior on a subsequent test for acquisition of morphine-seeking behavior.

Latency to first naloxone-induced jump as a measure of precipitated abstinence intensity in morphine-dependent mice and the interaction of set on this test

A method developed in this laboratory uses latency to time of first jump after injection of naloxone rather than the number of jumps in a specified period or the number of animals jumping as a measure of the degree of morphine physical dependence. For the test, mice are placed in a glass cylinder used as a test chamber, after being injected with the antagonist. During the development of this method it was observed that repeated exposures of dependent mice to both naloxone and the chamber yielded shorter latencies to first jump than did repeated exposures to naloxone alone in animals with the same degree of physical dependence. It appears that learning develops when naloxone injections are given repeatedly and followed by exposure to the test chamber and that this learned behavior is manifested by a reduced latency to first jump which may be confused with increased intensity of the opiate-withdrawal syndrome.

ROLE OF POSSIBLE IMMUNE MECHANISMS IN THE DEVELOPMENT OF TOLERANCE

Although a number of chapters in this book deal with various aspects of tolerance (see Chapters 19 and 20), it would be extremely difficult to discuss some possible mechanisms involved in the development of tolerance without briefly reviewing the major theories that have been proposed to explain this puzzling and intriguing phenomenon.