The opioid peptide dynorphin, circadian rhythms, and starvation.

Dynorphin, an opioid peptide whose functions are unknown, is found in brain, pituitary, and peripheral organs. Specific radioimmunoassays were used to measure dynorphin in the hypothalamus and pituitary, during the day and at night, as a function of food and water deprivation. Immunoreactive dynorphin was increased in the hypothalamus and decreased in the pituitary at night. Water deprivation led to more than 50 percent reduction in daytime levels of pituitary dynorphin and concomitant increases in hypothalamic dynorphin.

Endogenous opioid peptides and regulation of drinking and feeding.

Considerable work across the last 10 yr has implicated the endogenous opioid peptides in the regulation of ingestion. The opioid antagonists, such as naloxone and naltrexone, reduce intake of water, flavored water, and food. Naloxone's effects are pharmacologically specific, ie, its effects are dose-related and stereoselective. Further, a variety of antagonists produce similar effects. A primary site of action of naloxone, with respect to intake, is in the central nervous system. Naloxone's effects are also behaviorally specific, ie, its effects seem particularly related to palatability functions. The effects of opioid agonists, in small doses, enhance intake of some nutrients, but these effects are not opposite those of the antagonists. Benzodiazepines enhance drinking and eating and apparently interact with opioid systems. These observations combine with those directly measuring features of the endogenous opioid peptides to support a conclusion that opioid peptides are part of a system for regulating ingestion.

Cocaine self-administration and naltrindole, a delta-selective opioid antagonist.

Recent reports from several laboratories have suggested a role for delta opioid receptors in expressing some of the biochemical and behavioral effects of cocaine. Here, this possibility has been further explored by evaluating the propensity of rats to self-administer i.v. cocaine in the absence or presence of naltrindole, a selective delta opioid antagonist. Following a number of days of stable cocaine intake, and before a day's session, naltrindole (3 or 10 mg kg-1) reduced pressing for cocaine, regardless of the schedule of reinforcement. These data further support the role of processes associated with delta opioid receptors in the ability of cocaine to reinforce its own use.

Selected opioids and responding for intracranial reinforcement.

Rats fixed with chronically indwelling electrodes for intracranial stimulation (ICS) of the lateral hypothalamus pressed a lever during daily sessions for a fixed intensity of ICS. Before some sessions, they were given placebo, or ethylketocyclazocine (EKC) in racemic or isomeric forms [either (+)EKC or (-)EKC]. Naloxone (NX) was also given with the agents. The racemate facilitated pressing across a narrow range of small doses (centered about 0.02 mg/kg). At no dose did (-)EKC, a potent analgesic, facilitate pressing and typically depressed it. (+)EKC, at doses of 0.04 and 0.08 mg/kg, facilited pressing. These data provide further confirmation that opioid analgesia and ability to enhance pressing are separable. When NX was given with a large dose of the racemate, paradoxically pressing for ICS was facilitated. Apparently, NX selectively blocked the effects of (-)EKC. SKF 10047 was also administered in racemic and isomeric forms. All three forms produced some facilitation of pressing at small doses (e.g., 0.75 mg/kg) and depressed pressing at large doses (e.g., 5.0 mg/kg).

The role of the mediobasal arcuate hypothalamus in relation to opioid systems in the control of ingestive behaviour in the rat.

Bilateral, radiofrequency lesions of the mediobasal arcuate hypothalamus (MBH) strongly depleted levels of immunoreactive (ir)-beta-endorphin (beta-EP) in the hypothalamus and other brain tissues: these changes reflect destruction of those beta-EP-containing perikarya which are located in the MBH. No change in plasma ir-beta-EP was seen. The ir-dynorphin (DYN) content of the hypothalamus was also depressed while that of ir-Met-enkephalin was unaffected. The fall in hypothalamic ir-beta-EP was correlated with the fall in that of ir-DYN. Lesioned rats displayed only a minor, transient reduction in rate of weight gain between days 3 and 9 postsurgery: this disappeared thereafter. Further, the lesion did not affect the pattern of weight loss and regain associated with 24 h food and water deprivation. Indeed, the total 24 h (daily) food intake (FI) and water intake (WI) of lesioned rats did not differ from that of sham animals while deprivation-induced hyperphagia and hyperdipsia was not attenuated by the lesions. Moreover, the ability of naltrexone to decrease FI and WI (during both dark and light phases of the daily cycle) was not altered by the lesions. These observations indicate that central beta-EP may not be essential for the maintenance of a normal 24 h FI and WI and that opioid antagonists do not act upon the MBH or upon central beta-EP neurones in their suppression of FI and WI. Further, they suggest that central beta-EP may not fulfil an essential role in the control of body weight in the rat. Lesioned rats did, however, reveal a shift in the diurnal rhythmicity of FI and WI reflected in a reduction in the dark:light ratios of these. An alteration in the diurnal rhythmicity of sleeping and core temperature, but not locomotor activity, was also seen. The shifts in hypothalamic ir-beta-EP and ir-DYN (but no other tissue levels of any peptide) were correlated with the magnitude of the shifts in diurnal rhythmicity of ingestive behaviour. Moreover, lesions caudal to the MBH (not affecting hypothalamic ir-beta-EP or ir-DYN) or dexamethasone treatment (which affects pituitary pools of ir-beta-EP and ir-DYN) did not modify these rhythms. Thus, in these respects, the effects are 'particular' to MBH lesions modifying hypothalamic ir-beta-EP and ir-DYN. The data suggest that the MBH may play a role in the modulation of the diurnal scheduling of ingestive behaviour in the rat.(ABSTRACT TRUNCATED AT 400 WORDS)

Intracranial self-stimulation effects along the route of the nigro-striatal bundle.

Recent evidence suggesting a possible dopaminergic nigro-striatal substrate of self-stimulation led us to map this route for both self-stimulation and stimulus-bound motor effects. The results of 128 electrode placements show that the route of the nigro-striatal projection supports strong self-stimulation effects from the substantia nigra to the ento-peduncular nucleus. Beyond this level, such effects disappear. Our results indicate that the striatum itself is neutral with regard to reinforcement, and suggest that such apparent neutrality cannot be ascribed to motor or other artifacts. These findings require a reappraisal of the hypothesis of a dopaminergic self-stimulation system, although they are not in conflict with the idea that dopaminergic manipulations may affect self-stimulation through some more general regulatory influence on operant responding.

Cocaine place preference is blocked by the delta-opioid receptor antagonist, naltrindole.

Naltrindole, a selective delta-opioid receptor antagonist, was evaluated for its potential to block the reinforcing properties of cocaine using a conditioned place pairing paradigm in Lewis rats. Cocaine HCl (15 mg/kg s.c.) produced a strong place preference which was significantly blocked in animals pretreated with naltrindole (3 mg/kg i.p.); naltrindole alone showed no reinforcing or aversive effects. The results suggest a novel approach for the treatment of cocaine abuse in man.

Demonstrating morphine's potentiating effects on sucrose-intake.

Mildly deprived rats (18-hr of deprivation of water) were given the opportunity to take a solution of sucrose daily for periods of either 10, 18, 31, 56, or 100 min. After daily intakes stabilized and prior to a session, rats were given an injection of either morphine sulfate, 1.0 mg/kg, or naloxone hydrochloride, 2.5 mg/kg, an agonist and an antagonist, respectively, at the opioid receptors. Naloxone, as expected, decreased intakes regardless of the test-session's length. Morphine decreased intakes of the shorter sessions, but increased intake of the longest session. Subsequently, injections of morphine were given 56 min into a 100-min session. These injections also increased intake. Morphine's effects in potentiating intake seem to have special relevance with respect to the continuance of ingestion. Variations across experiments, in duration of test-sessions, could account for the variations in conclusions drawn about whether or not morphine and other agonists potentiate intake of ingesta.

alpha(2)-Adrenoceptor antagonists and propensity to take alcoholic beverages.

Rats were maintained on a daily regimen involving a 2h opportunity to take both water and a sweetened alcoholic beverage (12% ethanol, 0.25% saccharin). After 3 weeks on this regimen, rats regularly take substantial amounts of alcohol. After stabilization, injections of alpha(2)-adrenergic antagonists were administered, 15min before the opportunity to drink. Yohimbine and methoxyidazoxan dose relatedly decreased intake of alcoholic beverage and increased intake of water. In Experiment 2, a number of rats were taken off the daily regimen for 9 days, then returned to it. Across the first 12 days of the reinstated daily regimen, half the rats received placebo and half methoxyidazoxan. The group receiving placebo rapidly returned to taking large amounts of alcoholic beverage while the group receiving methoxyidazoxan did not. In Experiment 3, it was shown that a dose of methoxyidazoxan that decreased intakes of alcoholic beverage did not decrease intakes of other palatable beverages. In Experiment 4, it was shown that yohimbine persistently reduced intakes of alcoholic beverage with daily administration. These results indicate that alpha(2)-antagonists might be effective pharmaceutical adjuncts to other treatments for alcohol abuse and alcoholism.

Assaying addiction liability of opioids.

A number of procedures are available to assess an opioid's capacity to be positively reinforcing, but each has limitations that could lead to the false conclusion of no addiction potential. The recently developed conditioned place preference (CPP)-test, however, overcomes some of these limitations. Diprenorphine can be used to establish a CPP indicating it has an unsuspected capacity to elicit positive affect. Since diprenorphine antagonizes opioid analgesia and elicits signs of positive affect, the conclusion is confirmed that opioid analgesia and opioid's capacity to be positively reinforcing are separable.

Modulation of ethanol-intake by morphine: evidence for a central site of action.

Previous studies have shown that subcutaneous administration of low doses of morphine increase, while subcutaneous naloxone decreases, ethanol-intake in rats. However, the site of action of morphine modulation of ethanol-intake remains unclear. In an attempt to elucidate this issue, seven graded doses of morphine were given intracerebroventricularly to rats 15 min prior to an opportunity to consume water and sweetened alcoholic beverage for 2 hr. Two lower doses of intracerebroventricular morphine (1, 3 micrograms) reliably increased ethanol-intake, while higher doses (3-30 micrograms) decreased intake of water. Preference ratios (ethanol-intake divided by total fluid-intake) were reliably increased by morphine doses of 1 microgram and higher. The present data provide support for a central site of morphine modulation of ethanol-intake.

Opioidergic modulation of cocaine conditioned place preferences.

Recent studies have begun to assess the utility of opioid agonists and antagonists for the treatment of cocaine addiction. The present studies assess the effects of naltrexone or methadone on cocaine's reinforcing properties using the conditioned place preference (CPP) test. The results indicate that a 56 mg/kg dose of naltrexone, given 4 hr prior to conditioning, attenuates cocaine's CPP. In contrast, methadone (8 mg/kg), given 1 hr prior to conditioning, enhanced cocaine's reinforcing properties. These results support the suggestion that opioid antagonists may have clinical utility in treating cocaine addiction. The results with methadone lead to a possible explanation for the higher rates of cocaine use in methadone-treated heroin addicts.

Isradipine in combination with naltrexone as a medicine for treating cocaine abuse.

Rats were fixed with chronically indwelling electrodes for intracranial stimulation (ICS) of the medial forebrain bundle of the lateral hypothalamus. They were trained to press a bar in a Skinner box for the ICS. After stable rates of pressing for both a low and a high intensity of ICS were achieved during daily sessions, the rats were given doses of cocaine before the daily sessions. Cocaine produced its characteristic effect of enhancing rates of pressing. With continuance of daily sessions under the influence of cocaine, the rats received daily for 5 days a combination of isradipine and naltrexone. Doses of isradipine and naltrexone were smaller than a dose of either one that might modify pressing. The combination of isradipine and naltrexone blocked cocaine's enhancement of pressing for ICS. The same combination of isradipine and naltrexone did not reduce rates of pressing for ICS when cocaine was not given. These results indicate that a combination of isradipine and naltrexone is apt to be an effective pharmacological adjunct to other treatments for cocaine abuse.

Opioid antinociception and positive reinforcement are mediated by different types of opioid receptors.

Fentanyl (FEN) and diprenorphine's (DIPR) potentials for analgesia and reinforcement were assayed using rats. Analgesia was measured by the classic tail-flick test. The test germane to opioid reinforcement involved measuring pressing rates for direct electrical stimulation of the lateral hypothalamus and ventral tegmental area. FEN, as does morphine and heroin, produced strong analgesia and enhanced pressing rates for brain stimulation. DIPR produced no analgesia and antagonized FEN's analgesia. DIPR, at doses antagonizing FEN's analgesia, enhanced pressing for brain stimulation. DIPR's enhancement of pressing was antagonized by naloxone (100 micrograms/kg). When FEN and DIPR were given concurrently, pressing for brain stimulation was not reduced and was greater than after FEN alone was given. These data support a conclusion that different types of receptors are associated with opioid analgesia and reinforcement.

Endogenous opioids, circadian rhythms, nutrient deprivation, eating and drinking.

Immunoreactive (ir) beta-endorphin (b-END) and dynorphin (DYN) in rat brain and pituitary were measured after food and water deprivation and from brains taken during either day or night. In other rats, eating and drinking were measured following lesions in the arcuate n. Ir-DYN levels are higher in hypothalamus and lower in pituitary at night. Deprivation, particularly water deprivation, increases hypothalamic, day-time ir-DYN. Water deprivation decreases pituitary levels of ir-DYN. Arcuate-lesions, depleting both ir-b-END and ir-DYN, do not modify total daily intake of water or food but does modify circadian rhythmicity of eating and drinking. These data support the conclusion that b-END and DYN are involved in maintaining day-night patterns of eating and drinking.

Naltrindole, an opioid delta receptor antagonist, blocks cocaine-induced facilitation of responding for rewarding brain stimulation.

Recent experimental results have led to the suggestion that opioid antagonists can modulate the reinforcing properties of cocaine. In this experiment, rats were fixed with chronically indwelling bipolar electrodes for stimulation of the medial forebrain bundle (MFB) as it courses through the hypothalamus. Rats were taught to press a lever for brief trains of electrical stimulation of the MFB. Subsequently, they were allowed to press for varying intensities of stimulation daily until their response rates were stable. Cocaine (5 mg/kg, s.c.) enhanced the rate of pressing for lower intensities of brain stimulation. Naltrindole (3 mg/kg, i.p.) had no effect on response rate alone but blocked the cocaine-induced facilitation of pressing for rewarding brain stimulation. An implication that can be drawn from these data is that naltrindole, or other delta-selective opioid antagonists, might be effective as medicines for use in treating cocaine abuse.

Naloxone modifies sugar-water intake in rats drinking with open gastric fistulas.

The effects of the opiate antagonist naloxone (NX) on fluid preference and intake were determined in rats drinking with chronically indwelling gastric fistulas. The subjects were tested both after 22.5 hr fluid deprivation, and no deprivation, with open fistulas (sham drinking), as well as with closed fistulas. Following an injection of either saline or NX (0.5-10.0 mg/kg, administered SC), or no injection, the subjects were given the choice to drink water or 10% sucrose, in a two-bottle test, for 1 hr/day. With open fistulas, and following fluid deprivation, the animals sham drank both sucrose and water, but had a strong preference for sucrose. When not fluid deprived, the same animals sham drank sucrose almost exclusively. NX significantly reduced sucrose intake by the sham drinking animals, in both the deprived and not deprived conditions, but did not modify fluid preference. These data support the idea that NX modifies affective reactivity to palatable solutions, and that NX's antidipsogenic actions are not due to feedback from post-absorptional events.

Morphine and acceptability of putative reinforcers.

Rats were given the opportunity to take one of five concentrations of saccharin solutions. Intake across concentrations generated a preference-aversion curve. Morphine, 2 mg/kg, increased intake of saccharin solutions when rats were 12-hr water deprived or were not deprived. These effects with morphine are opposite to those of naloxone and strengthen the idea that there is opioid involvement in incentive motivation.

MDL72222, a serotonin 5-HT3 receptor antagonist, blocks MDMA's ability to establish a conditioned place preference.

Methylenedioxymethamphetamine (MDMA) has previously been shown to produce a positive conditioned place preference (CPP) among rats. Here the effects of doses of a specific 5-HT3 antagonist, MDL72222, on MDMA's ability to produce a CPP were assessed. A dose of MDL72222 (0.03 mg/kg) blocked the establishment of a MDMA CPP. These results support the suggestions that compounds affecting the 5-HT3 receptor may be of particular interest in studying the pharmacology of self-administered drugs.

Naloxone persistently modifies water-intake.

Rats, deprived of water for 19 hr, were given an opportunity to drink water for 30 min and for another 4.5 hr. Prior to drinking, rats were injected with saline or NX (2.5 mg/kg) to see if NX's effects persisted when given day after day. The findings confirmed that NX not only reduced intake but its effects showed no tolerance across consecutive administrations. Subsequently, when rats were deprived of water for 23.5 hr, NX produced a reliable decrease in intake. Intakes, however, were considerably greater than when subjects had an additional opportunity to drink.