Morphine-induced Taste Aversions Research Articles

Adolescent Fischer 344 and Lewis rats differ in morphine-induced taste aversions

Adolescent Fischer 344 and Lewis rats differ in morphine-induced taste aversions

A history of morphine-induced taste aversion learning fails to affect morphine-induced place preference conditioning in rats

Drugs of abuse have both rewarding and aversive effects, as indexed by the fact that they support place preferences and taste aversions, respectively. In the present study, we explored whether having a history with the aversive effects of morphine (via taste aversion conditioning) impacted the subsequent rewarding effects of morphine, as measured in the place preference design. In Experiment 1, rats were exposed to a taste aversion procedure in which saccharin was followed by morphine. Place preference conditioning was then initiated in which animals were injected with morphine and placed on one side of a two-chambered apparatus. Animals with a taste aversion history acquired place preferences to the same degree as controls without such a history, suggesting that morphine's affective properties condition multiple effects, dependent on the specific stimuli present during conditioning. To determine whether these results were a reflection of processes operating in traditional associative conditioning, in a modified blocking procedure, place preference conditioning was attempted in the presence of a taste previously associated with morphine (Exp. 2). Under these conditions, animals still acquired morphine-induced place preferences comparable to those of animals without a morphine or conditioning history. These results are consistent with the position that drugs of abuse have multiple stimulus effects (positive and negative) that are differentially associated with specific stimuli (environmental and taste) that drive different behavioral responses (approach and avoidance).

Assessment of the aversive effects of peripheral mu opioid receptor agonism in Fischer 344 and Lewis rats

The Fischer 344 (F344) and Lewis (LEW) inbred rat strains differ on a host of biochemical, neuroanatomical, immunological and behavioral endpoints. One behavioral difference of interest is their differential reactivity to the aversive effects of morphine as indexed by the conditioned taste aversion preparation (aversions acquired by F344 rats are significantly greater than those acquired by the LEW strain). This differential effect appears to be specific to opioids that work primarily on the mu opioid receptor. Given that morphine works systemically, it is unknown whether these differential effects in F344 and LEW animals are centrally or peripherally mediated. To address this issue, the present study investigated the ability of the peripherally acting mu preferring opioid agonist loperamide to induce differential taste aversions in F344 and LEW animals. Both F344 and LEW animals acquired dose-dependent taste aversions to the loperamide-associated solution with no difference between them. Additionally, control animals initially injected with vehicle during aversion training with loperamide and subsequently conditioned with morphine displayed the typical aversive profile to morphine (F344>LEW). Although the basis for the present data is unknown, their relation to morphine-induced taste aversions and the role of the interaction of stimulus effects of drugs that produce differential abuse liability were discussed.

The effects of light cycle phase on morphine-induced conditioned taste aversions in the Lewis, Fischer and Sprague-Dawley rat strains

The present experiment investigated the effect of light cycle phase on morphine-induced conditioned taste aversions in the Lewis (LEW), Fischer (F344) and Sprague-Dawley (SD) rat strains. Separate groups of rats from each strain were trained during either the light phase or the dark phase on a procedure in which saccharin was paired with one of two doses of morphine (or vehicle). With 3.2mg/kg morphine, strain differences were observed during the light phase, with F344 rats displaying a significantly stronger taste aversion than the LEW rats, who displayed a significantly stronger aversion than the SD rats. In contrast, during the dark phase, 3.2mg/kg morphine produced comparable, moderately strong aversions in all strains. With 10.0mg/kg morphine, F344 rats developed stronger aversions than either the LEW or SD rats in both phases of the light cycle. The effect of light cycle was most clearly seen in the SD rats, where stronger aversions were produced in the dark phase for both morphine doses. For the LEW rats, stronger aversions were produced in the dark as compared to the light only with the low dose of morphine. For the F344 rats, aversions of comparable strength were observed in both phases of the light cycle for both morphine doses. The finding that light cycle differentially affects morphine-induced taste aversions in these strains is consistent with what is known about strain differences in circadian patterns of corticosterone activity and with previous results relating corticosterone to morphine-induced taste aversions.

Naloxone, not proglumide or MK-801, alters effects of morphine preexposure on morphine-induced taste aversions

Both cholecystokinin (CCK) antagonists and N-methyl- d-aspartate (NMDA) antagonists block or reduce the development of morphine tolerance in several analgesic assays. The present experiments were performed to assess the ability of the CCK antagonist proglumide and the NMDA antagonist MK-801 to affect tolerance to the aversive properties of morphine as indexed by conditioned taste aversion (CTA) learning. Specifically, male Sprague–Dawley rats were exposed to either vehicle or morphine (5 mg/kg) in combination with either proglumide (5 mg/kg; Experiment 1), MK-801 (0.1 mg/kg; Experiment 2) or naloxone (1, 3.2 mg/kg; Experiment 3). Saccharin was then presented and was followed by an injection of either vehicle or morphine (10 mg/kg). Animals preexposed to and conditioned with morphine acquired an attenuated morphine-induced aversion to saccharin. While neither proglumide nor MK-801 had an effect on this attenuation, naloxone blocked the effects of morphine preexposure, suggesting that neither CCK nor NMDA may be involved in the aversive effects of morphine (or their modulation by drug exposure). That the attenuating effects of morphine preexposure on a morphine-induced CTA can be blocked suggests that the weakening of the aversive effects of morphine with chronic use can be prevented, an effect that may have implications for overall drug acceptability.

Morphine-induced conditioned taste aversions: assessment of sexual dimorphism

Although sex differences in taste aversions have been reported with emetics such as lithium chloride (LiCl), little is known whether such findings generalize to other aversion-inducing drugs, including recreational compounds. One particular class of recreational compounds that induces taste aversions but that has not been examined for sex differences in its aversive properties is the opioids. To assess sex differences in the aversive properties of the opioids, Experiment 1 examined the acquisition and extinction of morphine-induced taste aversions in male and female rats. To determine whether the specific parametric conditions used in Experiment 1 would support sex differences in general, Experiment 2 examined possible sex differences in the acquisition and extinction of LiCl-induced taste aversions, a compound for which sex differences have been previously reported. During acquisition, male and female rats were given 20-min access to a novel saccharin solution and injected with either morphine (0, 10, 18 and 32 mg/kg sc; Experiment 1) or LiCl (0, 0.3, 0.6 and 1.2 mEq sc; Experiment 2) every fourth day for a total of four conditioning trials. During extinction, subjects were allowed access to saccharin but were not injected (for a total of eight trials). There were no sex differences in acquisition with either morphine or LiCl. There were also no sex differences in extinction with morphine; however, sex differences were found with LiCl, an effect consistent with prior assessments with this drug. The basis for and implications of the differences in the effects of sex on morphine- and LiCl-induced taste aversions were discussed.

Morphine-induced conditioned taste aversions in the LEW/N and F344/N rat strains

Previous reports have shown that the LEW/N and F344/N inbred rat strains display a differential sensitivity to cocaine in a number of preparations, with the LEW/N rats displaying an increased sensitivity to both the reinforcing and aversive effects of cocaine (relative to the F344/N rats). Given that the LEW/N rats are also more sensitive to the reinforcing effects of morphine than the F344/N strain, the present experiment examined the ability of morphine to condition taste aversions in the LEW/N and F344/N strains to determine if the general sensitivity to cocaine generalizes to another drug of abuse. Specifically, on four conditioning trials, 35 LEW/N and 33 F344/N female rats were allowed access to a novel saccharin solution and then injected with varying doses of morphine (0, 10, 32 and 56 mg/kg). On intervening recovery days, subjects were allowed 20-min access to water. Following the fourth trial, a final aversion test was administered. The F344/N rats, but not the LEW/N rats, rapidly acquired morphine-induced taste aversions at all doses of morphine. Pharmacokinetic differences between the strains were also assessed. Specifically, 10 mg/kg morphine (or vehicle) was administered to subjects of both strains and plasma morphine levels were analyzed at 0.5, 2 and 4 h postinjection. No differences in plasma levels between the strains were observed. Unlike with cocaine, the LEW/N rats do not seem generally sensitive to morphine (relative to the F344/N rats). Rather, the differential sensitivity of the two strains to these compounds seems to be preparation dependent. Possible mechanisms underlying the differential sensitivity evident in the strains were discussed.

Conditioning of morphine-induced taste aversion and analgesia

The process of selective associations is evident in the aversive conditioning literature, where it has been shown that external cues are readily associated with peripheral pain, whereas taste cues are more easily associated with effects of drug administration. Within this framework, it is of interest that the failures to obtain a conditioned analgesic response to a morphine-associated CS have used external cues as conditioned stimuli. In Experiment 1, subjects re-exposed to a morphine-associated CS not only expressed the anticipated taste aversion, but also exhibited a decrease in pain sensitivity that was evident 15 or 30 min following CS re-exposure. Experiment 2 suggested that the conditioned analgesic response was opioid mediated, as pre-test administration of naloxone blocked expression of the analgesic CR. In Experiment 3, an increase in opiate receptor sensitivity produced by chronic naltrexone treatment did not affect the strength of the taste aversion, but resulted in an increase in the magnitude of the conditioned analgesic response. Collectively, these data suggest a neuropharmacological dissociation in systems mediating the two responses.

The effect of morphine preexposure on the acquisition of morphine-induced taste aversions: A nonassociative effect

In Experiment 1, the amount of time rats spent engaged in a range of behaviors was recorded immediately prior to and following the intraperitoneal administration of morphine sulfate (6 mg/kg) or distilled water. No behavioral differences were observed between these groups. In Experiment 2, preexposure to this low dose of morphine attenuated the subsequent acquisition of a morphine-induced taste aversion independent of the similarity of the preexposure and conditioning environments. These results with a dose of morphine that does not produce any behavioral effects, which in turn could potentially mask associative conditioning during preexposure, confirm that the attenuating effects of morphine preexposure on taste aversion learning are nonassociative.

Attenuation of the aversive and analgesic effects of morphine by repeated administration: Different mechanisms

Rats were repeatedly injected with a low (8 mg/kg) or high (40 mg/kg) dose of morphine during the preexposure phase of the experiment. They then received both taste-aversion training and morphine-induced analgesia assessment. These tasks were presented in the same environment or in a different environment from that associated with the drug during preexposure. Morphine preexposure attenuated morphine-induced taste aversion conditioning, whether or not the conditioning was conducted in the same environment as morphine preexposure. In contrast, the display of analgesic tolerance was more pronounced in the preexposed environment than in the alternative environment. These results suggest that repeated morphine administrations attenuate the aversive and analgesic effects of the drug by different mechanisms.

Heroin and morphine: Aversive and analgesic effects in rats

Although a number of studies demonstrate morphine-induced taste aversions, no such reports exist for heroin. In a conventional taste aversion paradigm, rats were injected with one of six heroin doses (0.5–12.0 mg/kg) after consuming a novel saccharin solution (Experiment 1). When the saccharin was reintroduced a second time no significant reduction in consumption occuredd at any of the doses tested. It was therefore concluded that heroin does not readily induce a taste aversion. In experiment 2, morphine was tested in an identical taste aversion paradigm and, as expected, a significant taste aversion.did result at two of the doses tested. Experiment 3 demonstrated that heroin produced analgesia equal to or greater than morphine when comparing dosages of heroin which failed to induce a CTA with CTA-inducing morphine dosages. Thus, whereas heroin is more potent than morphine as an analgesic, heroin is less potent than morphine as a CTA-inducing agent.

The effect of post-conditioning exposure to morphine on the retention of a morphine-induced conditioned taste aversion

In the following experiment, multiple injections of morphine sulfate following the acquisition of a morphine-induced taste aversion had no effect on the retention of the previously acquired aversion. Post-conditioning injections of morphine resulted in the development of physical dependence to morphine and led to a decrement in the ability of morphine to induce a subsequent aversion to a second novel taste. This failure of post-conditioning exposures to morphine to affect a previously acquired morphine-induced taste aversion even though tolerance to morphine had occured was discussed in the context of Rescorla's event-memory model of conditioning.

Morphine-induced taste aversions: A consideration of parameters

Following consumption of saccharin, groups of rats were injected with various doses of morphine sulfate. Although no aversion was found after one conditioning trial, repeated saccharin-morphine pairings resulted in decreases in consumption of the saccharin solution. On the average, however, the groups of rats showed only a moderate aversion, independent of the dose of morphine. Although there was little variability in consumption among rats that received the smallest dose of morphine, there was considerable individual variability among subjects receiving the larger doses. The differences between morphine-based conditioned taste aversions and aversions based on emetic USs were discussed.

Temporal analysis of naloxone attenuation of morphine-induced taste aversion

In a dose-response study, 7.5 mg/kg of naloxone produced maximal attenuation of conditioned taste aversion to saccharin induced by 10 mg/kg of morphine. Naloxone was administered immediately after the morphine in this study. In a second experiment, naloxone still caused a significant attenuation of taste aversions when administered with a 1 hr delay after morphine, but not after delays of 4 or 8 hr. These results suggest that behavioral consequences of morphine which peal during the first hr after injection (analgesia, catalepsy, and depression of intracranial self-stimulation) are not correlated with the aversive effect of morphine. Nor can the aversiveness of morphine be attributed to withdrawal effects. Only the facilitative actions of morphine occuring 1 to 4 hr after injection, including the facilitation of intracranial self-stimulation, are temporally correlated with the naloxone-sensitive aversive effect. Thus, a temporal analysis cannot be used to dissociate the paradoxical positive reinforcement and aversive effects of morphine. Rather, the temporal correlation between the two opposite motivational effects of morphine serves to emphasize the nature of this paradox.