What is learned during opiate withdrawal conditioning? Evidence for a cue avoidance model.

How conditioned opiate withdrawal gives rise to avoidance behaviour was examined using a defensive burying procedure in rats made dependent with a morphine pellet. The subjects underwent withdrawal precipitated by naloxone (0.1 mg/kg, SC) on two or three occasions in a box containing only a small object. When exposed to the object in the presence of sawdust one or more days later, the subjects avoided contact and buried this object, i.e., pushed and piled the sawdust against it. The behaviour was seen only when withdrawal had been paired with the object, which was the case even with a choice of objects on the test. Approach but no burying was seen in nondependent animals when the object was paired with 1 mg/kg morphine. Burying, therefore, was concluded to be a defensive response elicited in rats by an object specifically paired with precipitated opiate withdrawal. Consideration of burying and other defensive responses reported to be elicited by cues of withdrawal (conditioned place and taste aversion, and suppression), with respect to the behavioural demands of these responses and the test conditions needed to see them, suggested that a goal of avoidance may be a primary event encoded in a withdrawal cue, as is known for predictors of nonpharmacological noxious events (e.g., shock).

Log dose/response curve flattening in rats after daily injection of opiates.

Rats injected (IP) daily with 0, 20, and 200 mg/kg morphine-SO4 for 25-49 days experienced log dose/response (LDR) curve flattening (decrease in slope and/or maximum response) for analgesia (tail immersion test) produced by etorphine-HCl injected IP or intracerebroventricularly (ICV), and for latency to maximum rectal temperature increase produced by IP etorphine. Rats treated similarly with 0, 50, and 500 micrograms/kg etorphine-HCl for 32 days exhibited LDR-curve flattening for analgesia produced by etorphine and morphine (IP). In addition, a profound body weight loss produced by high-dose morphine treatment (200 mg/kg) was found not to be involved in flattening, since similar body weight decreases produced by food restriction in 0 and 20 mg/kg rats did not have this effect. Flattening, however, may be due to a rapidly acquired and rapidly lost within-session (acute) tolerance. When flattening was not seen at short intervals after IP or ICV test etorphine doses, flattening was seen when rats were retested at longer test intervals. Forty-eight hours after cessation of chronic etorphine treatment, flattening of the etorphine analgesia LDR curve was lost, but parallel shift was unaffected. Similarly, 200 mg/kg morphine-treated rats lost morphine tolerance more rapidly than 20 mg/kg-treated rats during the first 12 days after the last treatment injection. Subsequently, however, levels of the analgesia and the amounts of tolerance loss were comparable in both chronically treated groups. The data support the notion that chronic tolerance reflects an enhancement or prolongation of acute tolerance.

A taste aversion model of drug discrimination learning: training drug and condition influence rate of learning, sensitivity and drug specificity.

A model of drug discrimination based on a lithium chloride (LiCl) flavour aversion was described and examined. Mildly thirsty rats were presented daily with 4 ml of a distinctly flavoured solution which was followed on 50% of the days by an IP injection of LiCl. Prior to the flavour presentation, the rats were injection SC with saline or a training drug (0.04 mg/kg fentanyl or 20 mg/kg pentobarbital) to signal whether LiCl would follow. Almost all rats eventually exhibited stable behaviour that involved drinking most or all of the fluid when it was not to be followed by LiCl and little or no drinking when it was. Such discrimination occurred regardless of whether drug predicted LiCl (learned-discomfort) or predicted no LiCl (learned-safety). However, with fentanyl there were clear differences between rats trained with drug under learned-safety and under learned-discomfort conditions for 1) the rate of acquisition of stable performance as a function of LiCl dose, 2) generalization of the training dose to a test dose that was lower, and 3) elicitation of fentanyl responses by pentobarbital. These findings, together with indications that such effects did not always occur with pentobarbital as the training drug, were discussed from theoretical and practical perspectives.

Anxiogenic-like effects of opiate withdrawal seen in the fear-potentiated startle test, an interdisciplinary probe for drug-related motivational states.

RATIONALE: Anxiety-like effects may be universal to withdrawal from drugs of abuse. The study of withdrawal would benefit from the acoustic startle response (ASR), a discrete, cross-species reflex which is increased by fear-related states. However, existing reports of opiate-related effects on baseline ASR have not validated ASR as a measure of drug-related motivation. OBJECTIVE: The effects of opiate treatment and withdrawal were examined using fear-potentiated startle, a startle test more sensitive to fear than baseline changes. METHODS: Fear-conditioned rats were treated with Alzet osmotic pumps delivering 0.25 mg/kg per day fentanyl or placebo pumps. Experiment I examined changes before and during opiate treatment on locomotor activity and baseline, prepulse inhibition, and fear-potentiated startle. Experiment 2 examined the same responses during withdrawal precipitated after 4-7 days of treatment using IV naloxone. RESULTS: Experiment 1 revealed an attenuated fear-potentiated startle on the first test after the start of fentanyl treatment (4 h); this was not seen on subsequent tests and suggested tolerance to this acute effect. Experiment 2 found an enhancement of fear-potentiated startle precipitated in fentanyl-treated rats after injection of 0.025 and 0.16 mg/kg naloxone; this was not seen at 1 mg/kg naloxone, even though more physical withdrawal signs were most prevalent at this dose. In neither experiment did locomotor activity, baseline ASR, or prepulse inhibition of the ASR show any treatment effect. CONCLUSIONS: Fear-potentiated startle may provide a specific and valid measure of anxiety-like effects of drug withdrawal. Discussed were conditions needed to see this effect and the relevance of the findings for different mechanisms of withdrawal discomfort.

Aversive property of opioid receptor blockade in drug-naive mice.

The motivational effect of naloxone administration in the non-dependent laboratory mouse was examined with taste and place conditioning procedures. Thus, male CD1 mice without any history of drug exposure avoided a cue paired with three SC injections of as little as 0.1 mg/kg naloxone HCl. The aversive effect of naloxone was also seen in DBA/2 and C57BL/6 mice. In addition, it only occurred with the minus isomer and not the plus isomer, and it was potentiated by implantation, 3 days prior to training, of a morphine-containing (37.5 mg) but not a placebo pellet. Naloxone injection, therefore, acts as an aversive stimulus in naive mice and this is probably produced by decreases in activity of endogenous opioid peptide systems. Together with other data, the present results support the conclusion that the aversive effect of opioid receptor blockade in the opiate non-dependent organism may be general to a wide range of species including primates. The importance of training and testing variables for observing the naloxone aversive effect is discussed. Advantages of studying preference conditioning with mice are also given.

Motivational properties of kappa and mu opioid receptor agonists studied with place and taste preference conditioning.

The reinforcing properties of various opioid agonists acting preferentially on the kappa and mu opioid receptors were assessed using taste and place preference conditioning procedures. Kappa receptor agonists produced conditioned aversions. Taste aversions were produced by all of the drugs used, including racemic mixtures of ethylketazocine, tifluadom, and U50-488, and active isomers (+)-tifluadom, (-)-bremazocine, and Mr 2034; corresponding inactive isomers either produced no effect of were less potent. Place aversions were produced by U50-488 and (-)-bremazocine, but not (+)-bremazocine or any of the other kappa receptor agonists tested with the taste procedure. The mu agonists produced predominantly conditioned preferences. Place preferences were produced by morphine, fentanyl and sufentanil. Taste preferences were produced by low doses of these substances; at higher doses the taste preferences were absent or replaced by aversions. Finally, with naloxone and lithium chloride it was shown that the taste procedure was more sensitive to punishing effects than the place procedure. It is concluded that kappa and mu opioid receptor agonists are effective unconditioned stimuli. From the lower portions of the dose response curves it is further concluded that activation of kappa opioid receptors has aversive properties and activation of mu receptors appetitive reinforcing properties. The findings are also discussed with regard to the prevailing notions of taste conditioning with opiates, and the reinforcing properties of activity of the endogenous opioid peptide systems.

Naloxone prevention of morphine LDR curve flattening associated with high-dose tolerance.

Male wistar rats, previously made tolerant to morphine by at least 3 weeks of daily intraperitoneal (IP) injections of 20 mg/kg morphine-SO4 (MS), were then given 200 mg/kg MS daily for 4 or 5 days. Tail immersion tests of antinociception, carried out before and after the 200 mg/kg MS treatment, indicated that the additional morphine treatment, was followed by a large further decrease in opiate sensitivity, characterized by decreased slope of the log-dose/response curve (LDR curve flattening). The further decrease in opiate sensitivity was substantially reduced by naloxone-HCl (IP) in a dose of 10 mg/kg given 30 min before and 8 h after the 200 mg/kg MS injections, or a dose of 4 mg/kg given 45 min after the MS. It was concluded that LDR curve flattening produced by high doses of MS is mediated by specific opiate receptors, and is a true expression of a high degree of opiate tolerance in the intact rat.

Reinforcing properties of morphine and naloxone revealed by conditioned place preferences: a procedural examination.

In rats, conditioned place preferences are produced by morphine and conditioned place aversions produced by naloxone. In the present studies, several issues concerning the demonstration and interpretation of place conditioning findings were examined in a two-compartment (black and white) tilt box: (1) the responses of naive rats to testing, (2) place conditioning in rats with strong unconditioned biases to one of the sides, and (3) modifications of the testing situation so that naive rats respond to the black and white sides with a minimum of initial bias. Experiments involving manipulation of the conditions of training and testing, use of pentobarbital, and use of a three-compartment test box helped to control for morphine's ability to produce state dependent learning as an explanation of its conditioned place preference. In addition, we examined previous place conditioning studies that failed to show aversive effects of naloxone. These negative findings were suggested to be due to the use or procedures insensitive to aversive stimuli and to the IP administration of naloxone. Finally, in the course of the experiments, novel data on general parameters of the place conditioning were provided. Dose-response curves for subcutaneous (SC) morphine (0.04-5.0 mg/kg) and naloxone (0.02-5.0 mg/kg) were established. Conditioned preferences were also shown to occur after at three pairings of SC drug, and they were retained for at least 1 month.

Appetitive nature of drug cues confirmed with physiological measures in a model using pictures of smoking.

RATIONALE: In smokers, pictures of smoking that increase desire for a cigarette are described as pleasant rather than unpleasant. This suggests that these smoking cues may be appetitive and not withdrawal-like or aversive as held by traditional theories of drug cue formation. OBJECTIVE: Cues for smoking were examined using physiological measures of motivational valence. METHODS: Non-deprived smokers, deprived smokers and deprived smokers who expected to smoke (n=54) viewed a computer screen presenting experimental and control scenes (experiment 1). The acoustic startle reaction and activity of the corrugator and the zygomatic facial muscles were then measured after onset of smoking cues and standardized pleasant, neutral or unpleasant control scenes. Individuals who never smoked (n=18) were also used to test for cue effects on startle (experiment 2). RESULTS: No evidence was found that smoking cues were aversive in smokers. The smoking cues affected the startle responses and corrugator activity in a way similar to that of pleasant control material but significantly different from that of unpleasant material; the cue effects on zygomatic activity was most similar to that of neutral material. The general pattern of effects was not influenced by overnight smoke deprivation, expectancy to smoke or smoke repletion, but it was different in never smokers where the smoking scenes were found to be similar to unpleasant control scenes. CONCLUSIONS: Nonsubjective measures of motivational valence further suggest that drug cues are conditioned stimuli having appetitive effects. Startle response modulated by drug cues may be useful for probing motivational processes underlying dependence in the human.

Tolerance to hyperthermia produced by morphine in rat.

The present study addressed the prevailing notion that the rat develops tolerance only to the hypothermic effect of morphine and not to its hyperthermic effect. Rectal temperatures were measured at different intervals after various test doses of morphine in rats that had been rendered tolerant to morphine antinociception, by daily intraperitoneal injections of 0, 20, or 200 mg/kg morphine, and dependent, as seen by naloxone-produced loss of body weight. The well-known tolerance to the hypothermic effect was confirmed by changes in the dose-response curves for latency to peak hyperthermic response. In the falling arm of the test dose time/effect curve, consistent, clear decreases in morphine hyperthermia were seen. These decreases were proportional to the chronic treatment dose, and occurred in a normal test environment, where acute hypothermic effects were produced by morphine at short test intervals, and in a warm test environment, where no hypothermia was seen. Similar effects were noted when the data were analyzed in terms of area under the time/effect curve for hyperthermia. In the morphine-treated animals, decreased hyperthermia was seen despite serum morphine levels at the time of testing being up to twice as high as those in control rats. It was concluded that substantial tolerance develops to hyperthermia produced by opiates in rats. The previous difficulty in seeing this effect is discussed in regard to the probability that, in naive rats, the effect of morphine shortly after administration of a test dose reflects a summation of two opposing, acute thermic effects. The findings challenge the view that tolerance develops only to the depressant, and not to the excitatory, effects of opiates.

Infusion of gamma 2-MSH produce a conditioned taste aversion in morphine-dependent rats.

A two flavour, unbiased, taste preference conditioning procedure was used to test for possible motivating effects of gamma 2-MSH. Three training trials failed to produce any significant effect with doses ranging from 2.4 to 40 micrograms/ICV infusion in drug-naive, non-operated or placebo-implanted rats. However, in rats made dependent by SC implantation of a morphine pellet 4 days earlier 15 micrograms gamma 2-MSH/infusion produced a taste aversion that was comparable to that produced by infusion of a low dose of the competitive opioid receptor antagonist naloxone (0.32 micrograms). The findings confirm with a conditioning procedure and with opiate-dependent animals the naloxone-like effects of gamma 2-MSH. They also suggest that this endogenously-located peptide may acquire an aversive property as a result of chronic morphine treatment.

Loss of tolerance to morphine after a change in route of administration: control of within-session tolerance by interoceptive conditioned stimuli.

Tolerance to morphine analgesia (tail-immersion test) was examined after manipulation of two aspects of a tolerance test: 1) the route of drug administration and 2) the time interval between the test dosing and the tolerance test. The intravenous (IV) and intraperitoneal (IP) routes were used, together with a novel test for tolerance in which the test morphine was infused IV just 2 min before measuring the opiate effect. The first experiment validated this test as an assay for tolerance by examining the log dose-response (LDR) curve changes produced by daily IP injection with 0, 20 or 200 mg/kg morphine; the IV test confirmed the expected parallel shift to the right and flattening of the LDR curve. In the second experiment, all rats of two groups were injected once daily for 3 weeks with 20 mg/kg morphine and with saline except that one group received the morphine IV (and saline IP), the other morphine IP (saline IV). The results indicated route-specific tolerance. On a test using 20 mg/kg given IV morphine, tolerance was significantly greater in rats treated with IV morphine than in those treated IP. However, a larger effect on tolerance was produced by a pretest application of 5 mg/kg morphine 30 min before the actual tolerance test. This manipulation was designed to "prime" short-term, adaptive processes hypothesized to occur within a normal tolerance test session as morphine is taking effect. The tolerance on the test increased (equivalent to 2 to 3 fold shift in the LDR curve) when the pretest morphine was given with the same route as the chronic morphine, regardless of treatment group. It was concluded that opiate tolerance may be modulated by conditioned stimuli produced by morphine acting through different routes. These interoceptive cues appear to modulate rapidly acquired and short-lived adaptive processes taking place within a given test session.

Paced smoking in the laboratory and in the natural smoking setting: differential situation-specific effects in light and heavy smokers.

The present study examined the situation-specific effects of smoking using a paced regimen of smoking to control the smoke intake. The subjects were first required to sham smoke and then actually smoke one of their cigarettes in two different test contexts: 1) in the laboratory where they had never previously smoked and 2) at home, alone in a quiet room where they regularly smoke. Light (< 10 cigarettes/day) and heavy smokers (> 15 cigarettes/day) were studied to test for a possible effect of the paced regimen itself. In the light smokers, smoking produced a larger increase in heart rate (HR) in the laboratory than in the natural smoking environment; however, in the heavy smokers the smoking had a larger effect in the normal smoking environment than in the laboratory. There were no significant group or test situation differences for baseline HR, skin conductance and finger temperature. The groups also did not differ in the intensity of drawing on the cigarette or inhaling, as indicated by a puff sensor and a respiratory belt, respectively. It was concluded that differences between the effects of a cigarette in a laboratory setting and in a natural smoking environment may reflect pharmacodynamic effects of smoking that are modified by the subjects' prior experience with smoking. The data are discussed with regard to conditioned tolerance to the effect of smoking.

Modulation of craving by cues having differential overlap with pharmacological effect: evidence for cue approach in smokers and social drinkers.

RATIONALE: An increased risk of drug intake produced by drug cues may reflect the fact that the cues are withdrawal-like or aversive, reflecting a conditioned adaptation to the drug's acute effects. More recent work suggests that they may also be appetitive, signalling the goal characteristics of drug taking. OBJECTIVE: These opposing mechanisms were tested in dependent smokers and in social drinkers by examining the motivational nature of drug cues that overlap differentially with the acute effects of the drug. METHODS: Pictures of different phases of smoking or alcohol drinking were presented to deprived and non-deprived smokers, to never smokers and non-deprived smokers or to social drinkers. Desire for cigarettes or alcohol and momentary pleasure and arousal were measured after viewing an experimental picture or a pleasant, neutral or unpleasant control scene. RESULTS: High desire for smoking was evoked by pictures of preparation for and actual smoking but not by scenes of the end of smoking, although the latter were best correlated with acute drug effect. This pattern was not affected by overnight smoke deprivation, it was seen in different smokers but not in never-smokers and it was replicated in social drinkers using pictures of alcohol consumption. Moreover, scenes evoking high desire to consume did not evoke states of momentary unpleasantness and they were seen as relaxing and not arousing. Control pictures had a minimal effect on desire to consume. CONCLUSIONS: In line with incentive models of drug cues, cues based on pictures of drug intake may be conditioned stimuli encoding cue approach and preparation for consumption.

Aversive properties of naloxone in non-dependent (naive) rats may involve blockade of central beta-endorphin.

The present study examines the influence of destruction of the medio-basal arcuate hypothalamus (MBH), the primary site of synthesis of central pools of beta-endorphin (beta-EP), upon the aversive properties of naloxone in a conditioned place preference paradigm. Bilateral radiofrequency lesions of the MBH resulted in a pronounced fall in levels of immunoreactive beta-EP in the brain. Lesioned rats, in contrast to non-operated animals, showed a clear reduction in the conditioned place aversion produced by naloxone. However, they showed no loss of the conditioned preference produced by the mu-selective opioid receptor agonist, morphine, or the conditioned aversion produced by the kappa-selective agonist, U50-488. In contrast to the effect of the lesions, suppression of circulating beta-EP by dexamethasone treatment failed to influence conditioning produced by naloxone. Thus, the data indicate that the aversive properties of naloxone are attenuated by disruption of central (but not peripheral) beta-EP activity. We suggest that these properties of naloxone reflect an antagonism of beta-EP activity in the brain. In addition, the data indicate that differing mechanisms underlie the aversive actions of naloxone as compared to U50-488.

Appetitve effects of drug cues modelled by pictures of the intake ritual: generality of cue-modulated startle examined with inpatient alcoholics.

RATIONALE: A cue-modulated startle test recently confirmed that smoking cues in smokers may not be withdrawal-like and aversive as traditionally believed. OBJECTIVE: Analogous tests were applied to alcohol cues in inpatient alcoholics. METHODS: Twenty-six withdrawn alcoholics (18 men) were examined. Alcohol-related pictures were compared to standardised pleasant, neutral or unpleasant control scenes using an acoustic startle test and measures of pleasure, arousal and desire for alcohol. RESULTS: Pictures depicting preparation for drinking (cues) were different from unpleasant control pictures and similar to pleasant pictures but only on the startle test; no differential effects were found for alcohol craving and mixed motivational effects were reported subjectively. The effects were not due to arousal and control pictures depicting post-drinking events showed less effect than the alcohol cues. CONCLUSIONS: New techniques of measuring drug cue motivation indicate that drug cues may have incentive properties in individuals in treatment for alcoholism.

Is the motivational effect of opiate withdrawal reflected by common somatic indices of precipitated withdrawal? A place conditioning study in the rat.

Rats implanted for 5 days with a morphine pellet were dosed once with naltrexone (subcutaneous, s.c.) or methylnaltrexone (intraventricular, i.c.v.). Then the rats were observed for several somatic signs of precipitated withdrawal and tested for aversion to the place of the withdrawal. The two antagonist treatments produced different withdrawal syndromes, but both were associated with a place aversion which followed a simple monophasic function of the dose of antagonist. More importantly, there was an absence of any overall relation between individual withdrawal signs (jumping, writhing, shaking, diarrhea, and weight loss) and the aversive effect seen. It was concluded, therefore, that the motivational impact of opiate abstinence is not always addressed in conventional models of withdrawal.

Increased food intake after opioid microinjections into nucleus accumbens and ventral tegmental area of rat.

The nucleus accumbens (ACC) and ventral tegmental area (VTA), two areas believed to subserve reinforcement and increases in locomotor activity produced by opioid microinjections, were examined for their involvement in opioid-produced changes in ingestive behavior. Opioids were infused bilaterally, and food and water intakes were measured for 1 h thereafter. Different morphine doses were administered and, with placements in globus pallidus and lateral ventricles as controls for diffusion, it was found that only ACC and VTA microinjections (0.1-10 nmol) produced dose-related increases in food intake. In both the ACC and VTA low doses of morphine also produced increases in water intake while in ACC high doses produced a decrease. Administration of morphine and an enkephalin analogue (Tyr-D-Met-Gly-Phe(4-NO2)-Pro-NH2) at different depths in the ACC indicated that the increase in food intake occurred at a site separate from that of the decrease in water intake. Using levorphanol, dextrorphan and morphine mixed with naloxone, it was shown that the effects were due to activation of opioid receptors. Additional experiments demonstrated that food intake is increased by ACC morphine under different levels of deprivation, with different times of testing and with availabilities of various goal objects in addition to food. The effect also did not appear to undergo development of tolerance or sensitization. It was concluded that there are sites in the ACC and VTA where increased activity of endogenous opioid peptide systems reliably increase food intake and it was hypothesized that these sites may contribute to changes in ingestive behavior after systemic morphine administration. Also, together with other effects produced by opioid microinjections into the ACC and VTA, the present findings suggest that increased opioid activity in these areas produce a pattern of behaviors similar to that produced in normal animals by food conditioned stimuli.

Drug reinforcement studied by the use of place conditioning in rat.

Rats display a preference for an environment in which they previously received morphine. The present report provides behavioral and pharmacological data for this simple model of reinforcement produced by opiates and describes an aversion in rats for an environment in which they previously received naloxone. Preferences were produced with intravenous (i.v.) morphine sulfate at doses of 0.08-15 mg/kg and durations of the pairing between environment and morphine of 10 min to 1.5 h. Preferences were also seen with other opiate agonists (etorphine-HCl and levorphanol-tartrate), another route of drug administration (subcutaneous), and after 1-4 administrations of morphine. Cocaine-HCl (i.v.), a non-narcotic drug, known to be self-administered by humans, also produced a place preference. Lithium chloride (i.v.), an agent found to be a punishing stimulus in other situations, produced a place aversion. There was no appreciable preference for an environment paired with dextrorphan-tartrate and naloxone-HCl (2 mg/kg, i.p.) blocked the production of the preference produced by i.v. morphine. In contrast to the effect produced by morphine, aversions were produced with (-)-naloxone-HCl alone at doses of 0.1-45 mg/kg (i.v.). The aversion was not produced at (+)-naloxone. Implantation of rats with a 75 mg morphine pellet 3 days prior to place conditioning potentiated the aversive effect of naloxone. It was concluded that place conditioning produced by morphine and naloxone is mediated by specific opiate receptors and that stimulating and decreasing activity of the endogenous opioid peptide system with systemically administered drugs is positively reinforcing and aversive, respectively. The discussion emphasizes application of the simple and sensitive place conditioning model to drug reinforcement research, including analyses of reinforcement produced by microinjection of opiates into the brain.

Reinforcing effects of brain microinjections of morphine revealed by conditioned place preference.

The previously documented place conditioning paradigm was used to study the reinforcing effects of cerebral microinjections of morphine. Rats with implanted cannulae experienced place conditioning procedures, involving morphine administration into the IV (0.5 or 10 microgram), III (10 microgram) or lateral (0.5-10 microgram) ventricles. Positive reinforcement, indicated by a significant preference for the place paired with morphine compared to the place similarly paired with control treatment, was seen in rats given 10 microgram morphine into the lateral ventricle. The rats given 10 microgram into the III ventricle also showed a preference, but the effect was not statistically significant. Positive reinforcement was subsequently demonstrated with morphine microinjections (10 microgram) into the lateral hypothalamus, periaqueductal gray or nucleus accumbens. No clear preferences were produced by morphine injections into the caudate-putamen, amygdala or nucleus ambiguus. Following the final place conditioning test, rats were re-administered the treatment dose and analgesia and body temperature were measured. All three sites associated with reinforcement evidenced hyperthermia, but only the periaqueductal gray evidenced a short-latency analgesia. Sites with null place conditioning were not associated with any major behavioral effects. Using (+) and (-)-morphine (10 microgram), it was demonstrated that only the active (-)-stereoisomer was effective in producing place preferences after injection into the periaqueductal gray. It was concluded that morphine administered directly into parts of the rat brain can produce place conditioning similar to that seen after systematically administered morphine. Morphine-produced place preference is not related to the acute depressant aspects of morphine, but may be related to the stimulant aspects.