Control of morphine-withdrawal hypothermia by conditional stimuli

Male rats were given increasing doses of morphine sulfate to cause addiction. Each injection was paired with a bell. After a number of pairings, the bell acquired conditional-stimulus property in that, like morphine, it prevented withdrawal hypothermia during 72 h of withholding morphine. In another group the withdrawal hypothermia was precipitated by withholding of morphine injections. The bell reversed that hypothermia.     

Effect of dopaminergic stimulation or blockade on morphine-withdrawal aggression

The effects of morphine (10 mg/kg), nalorphine (1 and 10 mg/kg), and naloxone (1 mg/kg) were studied on the neocortical release of acetylcholine (ACh) in midpontine pretrigeminal transected rats. Morphine and, to a lesser extent, nalorphine decreased ACh release. Naloxone was ineffective alone but antagonized the action of morphine.Predoctoral fellow with scholarships from Laval University and Province of Quebec, Canada.This research was supported in part by USPHS grant MH-11846.     

Reduction of morphine-withdrawal aggression by conditional social stimuli

Sixty male hooded rats were made physically dependent on morphine by steadily increasing doses of morphine sulphate. A maintenance dose of 400 mg/kg/day was reached in 10 days and was continued for 5 additional days. At the end of the 15-day period all rats were withdrawn for 72 h and aggressive responses (attacks, rearing, and vocalization) were recorded for a 60-min period. One treatment group, in which a social experience had been paired with each morphine injection, showed significantly less morphine-withdrawal aggression than rats in two other groups which either remained socially isolated throughout the addiction period, or were grouped both at the time of morphine injection and during between-injection intervals.     

Effect of pharmacological blockade on lithium-induced water drinking

Administration of lithium chloride (40 mg/kg i.p.) led to a significant increase in 24 h water intake of rats. Prior administration of propranolol and haloperidol blocked the effect of lithium while atropine failed to show such an effect. The dipsogenic effect of lithium is probably exerted through beta-adrenergic and dopaminergic pathways.     

Effect of morphine antagonists on drug-induced hypothermia in mice and rats

The influence of pharmacological modifications of the functional activity of the central histaminergic system was studied on the susceptibility of mice to pentylenetetrazolinduced minimal (clonic) and maximal (tonic) seizures. Enhancement in the functional activity of the system by central administration of histamine or 4-methylhistamine or peripheral l-histidine loading failed to modify the risk of seizures. By contrast, reduction in histaminergic function was found to alter seizure susceptibility. Brocresine, an inhibitor of histamine synthesis, decreased and increased the risk of pentylenetetrazol-induced minimal and maximal seizures, respectively. Many, but not all, classical antihistamines (H₁ antagonists) and metiamide (H₂ antagonist) increased minimal seizure susceptibility after peripheral and intraventricular administration, respectively.     

The effect of morphine pretreatment on hypothermia induced by morphine in mice.

Morphine caused an apparently dose-dependent hypothermia in mice. Co-administration of naloxone antagonised this effect. Pretreatment with a single dose of morphine induced detectable tolerance to the hypothermic effect of a second dose of morphine given 3 h later and naloxone was more effective in antagonising the hypothermic effect of morphine in morphine-pretreated mice than in saline-pretreated animals. The present study has shown that morphine pretreatment can augment the antagonistic effect of naloxone towards the hypothermic action of morphine.     

The stimulus properties of morphine and ethanol

The present investigation sought (a) to establish the efficacy of morphine and ethanol as discriminative stimuli when each is paired with the administration of saline and (b) to compare, in a qualitative sense, the stimulus properties of the two drugs. Additional experiments examined the effects of treatment with naloxone or l-propranolol upon morphine and ethanol-mediated discriminated responding. Finally, the stereospecificity of the stimuli produced by morphine was determined by a comparison, in morphine-trained rats, of levorphanol and dextrorphan. Discriminated responding developed rapidly in both the morphine and ethanol groups. In tests in which ethanol was administered to morphine-trained animals and vice versa, no similarity to stimulus properties was apparent. Antagonism of discriminated responding induced by morphine and ethanol was attempted using naloxone and l-propranolol. Naloxone blocked the actions of morphine but was without effect upon ethanol. No evidence of antagonism of either drug by propranolol was found. When a range of doses of levorphanol (0.1–3 mg/kg) and dextrorphan (3–100 mg/kg) was tested in morphine trained animals, only levorphanol was able to substitute for morphine. The present results suggest that the stimulus properties of morphine represent typical opiate effects.     

Peripheral blockade of topical morphine tolerance by ketamine.

Repeated topical administration of morphine daily produces tolerance within three days. Ketamine alone has little effect in the radiant heat tailflick assay. However, with administered with morphine, topical ketamine prevented the development of morphine tolerance in a dose-dependent manner. Furthermore, topical ketamine also slowly reversed pre-existing morphine tolerance. These observations imply that topical morphine tolerance is mediated, at least in part, through peripheral N-methyl-D-aspartate (NMDA) receptors and raises the possibility of the use of topical NMDA receptor antagonists clinically.     

Naloxone produces hypothermia in rats pretreated with beta-endorphin and morphine

The effects of naloxone (an antagonist of opioids at opiate receptors) on the thermoregulatory responses were assessed in three groups of naive (saline-treated), morphine-tolerant (24 hr after a dose of 100 mg/kg (s.c.) of morphine-oil suspension or three doses of 100 mg/kg (i.p.) of morphine and beta-endorphin-tolerant (24 hr after an intraventricular dose of 100 μg of beta-endorphin) rats at an ambient temperature of 22°C. Both morphine and beta-endorphin produced hypothermia, catatonia and sedation in naive rats. The hypothermia was due to decreased metabolic rate and cutaneous vasodilation. However, both in morphine-tolerant and beta-endorphin-tolerant rats, morphine and betaendorphin each produced hyperthermia rather than hypothermia. There were no changes in behavior. The hyperthermia was due to increased metabolism. Furthermore, naloxone administration produced a dose-dependent hypothermia and abstinence syndrome in both morphine-tolerant and beta-endorphin-tolerant rats, but not in naive rats. The hypothermia in response to naloxone in opioid-tolerant rats was brought about by both decreased metabolism and cutaneous vasodilatation. The data indicate that pretreatment of rats with opioids alters the thermoregulatory effects of naloxone.     

Effect of gonadectomy on discriminative stimulus effects of morphine in female versus male rats

In a previous study, we found sex differences in the potency of morphine as a discriminative stimulus; the present study was designed to determine whether sex differences in gonadal hormones contribute to sex differences in morphine's discriminative effects. Adult female and male rats were gonadectomized (GNDZ) or sham-gonadectomized (SHAM), and then trained to discriminate 3.0 mg/kg morphine from saline. The ED50 for morphine discrimination was significantly lower in females than in males (0.66 +/- 0.12 vs. 1.25 +/- 0.16 mg/kg, respectively); ED50 values in GNDZ rats were slightly higher than in SHAM rats. The time course of morphine discrimination was not significantly different in females and males, whether GNDZ or not. The micro agonist fentanyl completely substituted for morphine in all rats, with no group differences in ED50 value. The micro agonists buprenorphine and nalbuphine substituted for morphine in nearly all females and in all SHAM males, but in only four of seven GNDZ males. The kappa agonist U69,593 did not substitute for morphine in rats of any group. Most opioid agonists were significantly more potent in decreasing response rate in males than females, and in GNDZ than SHAM rats; morphine and nalbuphine also increased response rate above control in some females. A pA2 analysis of naltrexone in combination with morphine suggested that there were no significant differences among groups in receptors at which morphine produced its discriminative stimulus effects. Although hormone replacement in GNDZ female rats at the end of the study reinstated estrous cycling, it did not substantially alter the ED50 for morphine discrimination. Thus, sex differences in potency of morphine as a discriminative stimulus may not be due to sex differences in gonadal hormone milieu. The possibility that sex differences in reinforcement frequency on morphine versus saline levers caused the sex differences in morphine discrimination is discussed.     

Attenuation of the discriminative stimulus strength of morphine by haloperidol.

Rats were trained to lever press on an FR 10 schedule of food reinforcement, and to respond differentially on two levers while discriminating the effects of morphine (10 mg/kg) from those of saline (1 ml/kg) injection. In these rats, the discriminability of morphine was reduced by pretreatment with haloperidol (0.32 mg/kg).     

Effects of morphine and nalorphine on kainic acid-induced hypothermia in rats

Intraventricular administration of kainic acid at the dose of 0.1 g induces a significant depression of rectal temperature followed rapidly by its slight elevation. Morphine (40.0 mg·kg^-1 IP), which by itself elicited biphasic effect on the body temperature of rats—initially hypothermia followed by hyperthermia—slightly increased the kainic acid-induced hypothermia. Kainic acid did not cause any changes in the hyperthermic effect of low doses of morphine (10.0 mg·kg^-1). Pretreatment of rats with nalorphine enhanced the kainic acid-induced hypothermia. On the contrary, nalorphine reversed the hypothermic effect produced by morphine at the dose of 40.0 mg·kg^-1. The results suggest that morphine and kainic acid-induced hypothermia are not mediated by the influence on the same type of receptors.     

Temporal and environmental cues in conditioned hypothermia and hyperthermia associated with morphine

The effectiveness of temporal and environmental cues in eliciting conditioned hypothermia and hyperthermia was studied in male Wistar rats using as an unconditioned stimulus an IP injection of 20 mg/kg of morphine sulfate. The relevance of temporal stimuli was minimized in Experiment 1 by administering morphine at irregular times on alternate days. For one group (Cond) morphine injections were preceded and followed by periods in distinctive environments. Group Pseudo animals, though exposed to the environments, received morphine on the intervening days in the home cage; group Saline received only saline. All animals receiving morphine showed a non-specific hypothermia when not under the direct influence of morphine. A conditioned hyperthermia was evident in group Cond animals in the distinctive environments. In Experiment 2, in which animals remained in their home cages at all times, the releavance of temporal cues was emphasized by administering morphine at exactly 24 h intervals. These animals became hypothermic only around the time of the expected injection. Animals in another group that received morphine at irregular times showed the non-specific hypothermia seen previously. There was no evidence for a conditioned hyperthermia in this second experiment.     

Behavioral and neuropharmacological characterization of nicotine as a conditional stimulus

In rats, the pharmacological (interoceptive) effects of 0.4 mg/kg nicotine can serve as a conditional stimulus in a Pavlovian conditioning task. Nicotine administration is paired with intermittent access to a liquid sucrose unconditional stimulus; sucrose is withheld on saline sessions. An increase in sucrose receptacle entries (goal tracking) on nicotine sessions indicates conditioning. Rats were trained on a nicotine dose ((-)-1-Methyl-2-(3-pyridyl)pyrrolidine; 0.1, 0.2, or 0.4 mg base/kg, s.c.). Generalization was examined using 0.025, 0.05, 0.1, 0.2, and 0.4 mg/kg nicotine and saline. Some behavioral effects of nicotine have been attributed to dopamine and glutamate. Accordingly, potential blockade of the nicotine cue via the dopamine system was examined by administering (R)-(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390; 0.005, 0.01, and 0.03 mg/kg), 3-Chloro-5-ethyl-N-[[(2S)-1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2-methoxy-benzamide hydrochloride (eticlopride; 0.01, 0.03, 0.1, and 0.3 mg/kg), or N-[(1-Butyl-2-pyrrolidinyl)methyl]-4-cyano-1-methoxy-2-naphthalenecarboxamide (nafadotride; 0.03, 0.1, 0.3, 1, and 3 mg/kg) before nicotine. 2-Methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP; 0.3, 1, and 3 mg/kg) and (5S,10R)-(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801; 0.01, 0.03, 0.1, and 0.2 mg/kg; dizocilpine) were used to examine possible glutamatergic components. Substitution tests were conducted with MPEP and nafadotride. Differential conditioned responding was acquired in the 3 groups. Conditioned responding generally decreased as the nicotine test dose moved away from the training dose; responding increased when 0.4 mg/kg trained rats were tested with 0.2 mg/kg. SCH-23390, eticlopride, nafadotride, and MPEP decreased conditioned responding on nicotine at doses that also decreased chamber activity. In contrast, MK-801 decreased goal tracking on nicotine without decreasing chamber activity, indicating a role for N-methyl-D-aspartate receptors in expression of nicotine-evoked conditioned responding.     

A comparison of testing procedures on the discriminative morphine stimulus

The study investigated the effects of reinforcement and non-reinforcement during test sessions, and the effects of duration of generalization test sessions on the generalization of a morphine-induced discriminative stimulus. Rats were trained to discriminate 3 mg/kg morphine from saline in a two-lever drug discrimination task and were then tested for generalization of 0, 1, 2, 3, 4, and 5 mg/kg morphine with the training drug under both reinforced and non-reinforced contingencies during 4-min test periods. The percentage of drug-appropriate responses and response rates were recorded for the first 2 min and the second 2 min of each test session. A higher proportion of drug-appropriate responding occurred with an intermediate dose of morphine when reinforcement was available during test sessions. The frequency of responding was higher during the last 2 min than during the first 2 min of reinforced test sessions. The changes in response rate observed between the first 2 min and the last 2 min of the test sessions also depended on the reinforcement contingency available and the dose of morphine administered presession. The testing parameters thus altered the degree of generalization and the shape of the generalization curve of the morphine discrimination.     

Effect of 5-HT3 receptor antagonists on the discriminative stimulus properties of morphine in rats

5-HT₃ receptor antagonists, e.g. MDL72222, ondansetron and ICS205-930, have been previously reported to block a morphine (1.5 mg/kg)-induced conditioned place preference in rats. This finding suggests that these drugs may modify the morphine discriminative stimulus which underlies place conditioning. To study this further we have examined the effects of MDL72222, ondansetron and ICS205-930 against a morphine discriminative stimulus using a two-choice, food reinforced, operant paradigm. In an attempt to provide consistency with previous place conditioning studies, a morphine training dose of 1.5 mg/kg was used in addition to a higher 3 mg/kg dose which was studied in separate animals. Stimulus control of behaviour was attained at both morphine training doses, the characteristics of each being consistent with an effect at the mu opioid receptor. Ondansetron (0.001–1 mg/kg), MDL72222 (0.1–3 mg/kg), and ICS205-930 (0.001–1 mg/kg) all failed to consistently antagonise the morphine cue at both training doses, although a mild attenuation was seen in the 1.5 mg/kg group following pretreatment with an intermediate dose of ondansetron and ICS205-930 (both 0.01 mg/kg). The present results therefore suggest hat 5-HT₃ antagonists do not block a morphine discriminative state, at least in rats.     

Abuse potential and pharmacological comparison of tramadol and morphine

The purpose of the study was to assess the abuse potential of the opioid analgesic tramadol. Tramadol (75, 150 and 300 mg), morphine (15 and 30 mg) and placebo were tested intramuscularly in volunteer non-dependent opiate abusers. Subjective, behavioral and miotic changes were assessed prior to dosing and intermittently for 12 h after drug administration. Morphine produced typical subjective effects, opiate identifications and miosis. Tramadol 75 and 150 mg were not different from placebo. Although tramadol 300 mg was identified as an opiate, it produced no other morphine-like effects. These findings suggest that tramadol has a low abuse potential by the parenteral route.