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Calcitonin gene-related peptide (CGRP), which has been observed in different parts of the nervous system, is known to modify pain sensitivity to different stimuli in rats and mice. The aim of this study was to investigate the possible interaction of CGRP with morphine on nociception in adult male NMRI mice after central administration of the peptide. CGRP (20 or 200 ng) did not itself modify pain sensitivity in the tail-flick test and did not affect the acute antinociceptive action of a single dose of morphine in the same test. However, CGRP suppressed the development of rapid tolerance to morphine in a dose-dependent manner, but had no action on the development of chronic tolerance to morphine and on manifestations of naloxone-precipitated withdrawal syndrome.

The development of cross-tolerance to an analgesic effect was observed between two mu-receptor agonists, heroin and fentanyl. Repeated treatments with heroin twice a day for 4 days resulted in a decreased nociceptive effect to fentanyl on day 5. The fentanyl dose-response line shifted to the right, and was considered to be a sign of the development of cross-tolerance. Peripheral treatment with oxytocin did not block the development of heroin-fentanyl cross-tolerance. However, intracerebroventricular administration of oxytocin blocked the development of tolerance, causing a leftward shift in the dose-response curve and supporting the assumption that oxytocin blocks the development of heroin-fentanyl cross-tolerance via CNS mechanisms.

The effects of intracerebroventricularly (ICV) administered secretin on the analgesic, tolerance-inducing, and dependence-inducing actions of morphine were investigated, in adult, male CFLP mice. Secretin administered doses ICV did not itself affect pain sensitivity in a heat-radiant tail flick test. However, it depressed the acute nociceptive effect of a single subcutaneous (SC) dose of morphine (4 mg/kg) after ICV (1 or 10 ng/animal) secretin administration. A dose of 10 ng secretin facilitated the development of acute morphine tolerance. On the other hand, none of the doses applied had any influence on chronic morphine tolerance, where animals were implanted SC with a morphine- containing pellet and the pain sensitivity was measured 3 days later. Morphine withdrawal signs were also evaluated by injecting naloxone. In a 100-ng dose, secretin increased the latency of the withdrawal jumping response; the peptide did not modify the other abstinence signs. These data suggest that central secretin administration can modify the analgesic effect of morphine.

It has previously been demonstrated that cocaine stimulates the hypothalamic-pituitary-adrenal (HPA) axis through hypothalamic corticotropin-releasing factor (CRF) secretion. The role of different neurotransmitters in mediation of the cocaine-induced elevation of plasma corticosterone (CORT) were investigated in rats by using transmitter antagonists. Peripheral (IP) pretreatment with a dopaminergic antagonist, pimozide (0.01-1.0 mg/kg, IP), a noradrenergic blocker, phenoxybenzamine (1.0-4.0 mg/kg, IP), a beta-adrenergic blocker, propranolol (0.2-10 mg/kg, IP), an opiate antagonist, naloxone (1.0-4.0 mg/kg, IP), and a muscarinic cholinergic antagonist, atropine (1.0-4.0 mg/kg, IP), inhibited the cocaine-induced CORT response dose dependently. A similar dose-dependent inhibition of the plasma CORT response induced by cocaine was observed after the ICV route of administration of these antagonists in microgram quantities. None of the investigated IP or ICV doses of transmitter antagonists altered the basal CORT level. These results suggest that the activation of multiple neurotransmitter systems, including catecholaminergic, opiate, and cholinergic systems, might be responsible for the cocaine-induced HPA axis activation, probably through the specific receptors located in the CNS.

Subchronic administration of cocaine induces behavioral sensitization (increasing hypermotility) to a challenge dose of the drug administered 72 h after the cessation of treatment. The effects of repeated administration of the neurohypophyseal hormones oxytocin (OXT) and arginine8-vasopressin (AVP) on the development of behavioral sensitization induced by subchronic treatment with cocaine were investigated in mice. Repeated treatment of OXT and AVP did not modify the locomotor stimulatory effect of the challenge dose of cocaine in cocaine-naive control animals. OXT in a dose of 0.5 microgram (sc) augmented the cocaine-induced behavioral sensitization. In contrast, AVP (0.005-0.5 microgram/mouse, sc) dose dependently attenuated the development of sensitization to the hypermotility-inducing effect of cocaine. The results suggest that the behavioral sensitization induced by cocaine can be modulated in opposite directions by neurohypophyseal hormones.

Atrial natriuretic peptide (ANP) is known to participate in different vegetative functions. The aim of the present study was to investigate the influence of ANP on nociception itself, pain sensitivity to morphine, and the development of acute and chronic tolerance to morphine. Morphine withdrawal signs were also evaluated by injecting naloxone. In adult, male NMRI mice, ANP administered SC or ICV did not affect pain sensitivity itself in a heat-radiant tail-flick test. Peptide treatment, however, depressed the acute nociceptive effect of a single dose of morphine (4 mg/kg, SC) after both SC (20-200 ng/animal) and ICV (5, 10, 20, or 200 ng/animal) ANP administration. ANP given SC and ICV attenuated the development of acute morphine tolerance. Acute morphine tolerance was assessed by giving a bolus injection of morphine (60 mg/kg) 24 h before the pain sensitivity to a challenge dose of morphine (4 mg/kg) was measured. ICV treatment with ANP also blocked the development of chronic morphine tolerance, but did not affect the appearance of naloxone-precipitated withdrawal syndromes. ANP seems to act differently on the development of tolerance to and dependence upon morphine.

The development of cross-tolerance to an analgesic effect has been observed between a mu-receptor agonist, heroin, and a delta-receptor agonist, Met2-Pro5-enkephalinamide. Repeated treatments with heroin twice a day for 4 days resulted in a decreased nociceptive effect to enkephalin on day 5. The enkephalin dose-response line was shifted to the right, considered a sign of the development of cross-tolerance. Peripheral treatment with oxytocin blocked the development of heroin-enkephalin cross-tolerance. A similar effect was observed after intracerebroventricular administration of oxytocin, supporting our assumption that oxytocin blocks the development of heroin-enkephalin cross-tolerance via CNS mechanisms.

The effects of a potent LH-RH receptor antagonist, [Ac-4-Cl-D-Phe1,2,D-Trp3,D-Arg6,D-Ala10]LH-RH (ORG 30276), on the behavioral actions of the LH-RH agonist, D-Trp-6-LH-RH, were studied in mice. The subcutaneous (SC) administration of 100 micrograms/kg D-Trp-6-LH-RH inhibited ambulation in an open-field, produced analgesia in the hot-plate and tail-flick tests. These effects of the agonist were totally antagonized by pretreatment with ORG 30276 at a dose of 100 micrograms/kg SC. In the apomorphine-induced cage-climbing test, both the agonist and the antagonist alone or together suppressed the duration of stereotyped behavior in dose-dependent manner, but, as there was no additive synergism after combined treatments, it seems that the two substances mutually diminish each other's effects. The results indicate that the behavioral effects of the LH-RH agonist can be antagonized by pretreatments with a potent LH-RH antagonist designed to block pituitary LH-RH receptors, with the exception of the suppression of apomorphine-induced cage-climbing, where special type of receptors and/or mechanisms might be involved.

In previous experiments, it was shown that rat atrial natriuretic peptide (rANP1-28) is able to increase the passive avoidance latency in a dose-dependent manner in the learning and consolidation phase (3). In order to clarify whether ANP has a direct action on this behavioral paradigm, or whether the action is mediated by neurotransmitters, rats were pretreated with different receptor blockers. The selected doses of the different receptor blockers could themselves not influence the behavioral paradigms. Haloperidol or atropine blocked the action of ANP on the consolidation of the passive avoidance response. Phenoxybenzamine, propranolol, methysergide, bicuculline and naloxone were ineffective. The data suggest that dopaminergic and cholinergic mediations are involved in the action of ANP on the passive avoidance response.

Different doses of rat atrial natriuretic peptide (rANP1-28) were tested as regards the extinction of active avoidance behavior following its injection into the lateral brain ventricle in rats. ANP delayed extinction of the active avoidance reflex in a dose-dependent manner. When the animals were pretreated with different receptor blockers in doses which themselves had no action on the extinction of active avoidance behavior, the action of ANP on this paradigm was completely blocked by haloperidol and atropine, whereas phenoxybenzamine/propranolol, naloxone, bicuculline and methysergide were ineffective. The data suggest that ANP delays the extinction of active avoidance behavior, and that cholinergic and dopaminergic transmitter systems might be involved in this action.

The dipeptide Z-prolyl-D-leucine (Z-Pro-D-Leu) has been demonstrated to inhibit the development of tolerance to and dependence on morphine in the mouse. Since the dipeptide affects dopamine (DA) utilization in the terminal regions of the mesolimbic and nigrostriatal DA-ergic projections, the question has been studied of whether DA-ergic mechanisms are involved in the action of Z-Pro-D-Leu on morphine withdrawal. Both inhibition of tyrosine hydroxylase by alpha-methyl-p-tyrosine (alpha-MPT) and inhibition of DA receptors by pimozide interfere with the effect of Z-Pro-D-Leu on naloxone-precipitated morphine withdrawal. Inhibition of serotonin (5-HT) synthesis by DL-p-chlorophenylalanine (PCPA), on the other hand, does not modify the effect of the dipeptide. The results argue for a role of DA-ergic mechanisms in the effect of Z-Pro-D-Leu on the development of morphine dependence.

In the present study the effects of somatostatin and cysteamine (a selective decreaser of the somatostatin level in the body) were compared in different behavioral tests on rats. Somatostatin inhibited the extinction of active avoidance behavior 8 hr and 24 hr after intracerebroventricular (ICV) treatment, while cysteamine facilitated it 4 hr and 8 hr after subcutaneous (SC) treatment. Somatostatin did not significantly influence the cysteamine-induced facilitation of the extinction. Somatostatin did not have a significant effect on T-maze spatial discrimination learning and reverse learning, whereas cysteamine markedly attenuated the performance 4 hr (1st day) after treatment. Somatostatin in a dose of 4 micrograms (ICV) increased the locomotor activity 10 min after treatment, while cysteamine markedly decreased all parameters of the open-field test. These effects of the drug had disappeared 24 hr after treatment. If different doses of somatostatin (4 micrograms or 10 micrograms ICV) were administered to cysteamine-pretreated rats, the peptide did not modify the drug-induced changes in the open-field test. The data suggest that the brain somatostatin might have a physiological role in the organization of certain types of behavior.

The action of H-Phe-Ile-Tyr-His-Ser-Tyr-Lys-OH on the passive and active avoidance behavior and open-field activity of rats was studied after peripheral and intracerebroventricular administration. When applied before the test session, intracerebroventricular administration increased the avoidance latency of passive avoidance behavior. Subcutaneous, intraperitoneal and intracerebroventricular administration of the peptide delayed the extinction of active avoidance behavior. Both subcutaneous and intracerebroventricular administration increased the grooming activity of the rats. The data suggest that H-Phe-Ile-Tyr-His-Ser-Tyr-Lys-OH is able to influence memory, acting mainly on the retrieval processes, and to modify open-field activity.

Performance of an active avoidance (bench-jumping) reflex has been studied in rats during stimulation of the midbrain raphe nuclei. Raphe stimulation (10 cps, 0.2 msec, 2.5-5.0 V) inhibited the performance of the reflex. A serotonin receptor blocker (methysergide, 2.0 mg/kg IP) increased the reflex performance in non-stimulated animals and prevented the action of raphe stimulation. The data indicate that the cerebral serotoninergic system might have an inhibitory control over the performance of conditioned avoidance reflex.

The synethetic dipeptide Z-Prolyl-D-Leucine (Z-Pro-D-Leu) inhibits the development of tolerance to and dependence on morphine in mice. The possible mode of action of the dipeptide was studied by measuring the alpha-MPT-induced disappearance of noradrenaline (NA) and dopamine (DA) either by a spectrofluorimetric assay in major brain areas (lower brainstem, striatum) or by a radioenzymatic assay in specific brain nuclei. For the latter purpose, mouse brain nuclei containing mainly the cell body areas (nucl. tractus solitarii, locus coeruleus, substantia nigra, area tegmentalis ventralis) or some selected terminal projections (nucl. caudatus, nucl. accumbens, gyrus dentatus hippocampi, nucl. raphe dorsalis) of major NA- and DA-containing pathways were selected. In the lower brainstem studied as a whole, the dipeptide did not affect the utilization of either NA or DA. Analysis of the data on the NA utilization in specific brain nuclei, however, revealed that the dipeptide affected NA disappearance in some mesencephalic-limbic nuclei which receive noradrenergic innervation from the dorsal noradrenergic bundle (e.g., nucl. raphe dorsalis, area tegmentalis ventralis, gyrus dentatus). NA utilization in the cell body region of the same pathway (locus coeruleus), however, was not affected by the dipeptide. The dipeptide facilitated DA utilization in the main terminal area of the mesolimbic DA-ergic projection (nucl. accumbens), whereas the same treatment inhibited DA utilization in the main terminal region of the nigro-striatal DA-ergic pathway (nucl. caudatus). The data suggest that localized changes in NA and DA utilization following Z-Pro-D-Leu might be important for peptide-induced changes in morphine tolerance and dependence.

The antiamnesic effects of prolyl-leucyl-glycinamide (PLG) and analogues of this tripeptide were investigated in rats. Retrograde amnesia was induced by electroconvulsive shock treatment and the degree of amnesia was characterized by the attenuation of one-trial learning passive avoidance response. PLG resulted in dose-dependent attenuation of retrograde amnesia. Structural modifications included N-terminal protection, substitution of the C-terminal NH2 group, replacement of the N-terminal amino acid, and replacement of the second amino acid of the tripeptide. Some tripeptides, all of them containing D-pipecolic acid instead of the N-terminal proline, were more effective than PLG. Therefore, D-pipecolic acid, D-pipecolamide and their N-terminally protected analogues were also investigated, and were found to have powerful antiamnesic effects.

The actions of blockers of dopaminergic receptors (haloperidol), alpha-receptors (phenoxybenzamine), beta-receptors (propranolol) and muscarinic cholinergic receptor (atropine) on the ACTH-induced delay of the extinction of active avoidance behavior were studied in rats. In the doses used, none of the receptor blockers modified the extinction of active avoidance behavior. ACTH delayed the extinction. However, the dopamine receptor blocker (haloperidol) and the muscarinic cholinergic receptor blocker (atropine) did prevent the action of ACTH in delaying the extinction of active avoidance behavior, whereas the alpha-(phenoxybenzamine) and beta- (propranolol) receptor blockers were ineffective. The results suggest that mainly dopaminergic and cholinergic mediations are involved in the delaying action of ACTH on the extinction of active avoidance behavior.

The repeated administration of beta-endorphin to mice resulted in the development of tolerance to the analgesic effect of the opioid peptide. While SC injections of oxytocin failed to modify the magnitude or the duration of the analgesic effect of a single intracerebroventricular (ICV) beta-endorphin injection, the development of tolerance to beta-endorphin was antagonized by SC and ICV oxytocin treatment. Since both oxytocin and beta-endorphin are endogenous peptides in the brain, the data raise the possibility that endogenous oxytocin might be involved in the sensitivity of the central nervous system towards repeated or prolonged opioid stimulation.

The effects of beta-[Tyr9]melanotropin-(9-18) on the extinction of the active avoidance reflex in (dopamine receptor blocker) haloperidol-treated animals, and on the open-field activity in haloperidol and amphetamine-treated rats were studied. It was shown that a systemically given 100 microgram dose of the peptide, which had no action on the ambulation and rearing activity in the open-field test, could still delay the extinction of the active avoidance reflex. Haloperidol treatment was able to partially block the effects of the ICV administered beta-[Tyr9]melanotropin-(9-18) on both the extinction and open-field activity. After intracerebroventricular administration, the effect of the peptide on the open-field test was partially similar to that of amphetamine: it facilitated the ambulation and rearing activity, and (in contrast with amphetamine) was able to facilitate the grooming activity, even in the presence of amphetamine. The results suggest that dopaminergic innervation might play a mediating role in the effect of beta-[Tyr9]melanotropin-(9-18) on the extinction of the active avoidance reflex and open-field activity. The effect on the open-field activity differens in part from that of amphetamine.

Cholecystokinin octapeptide (CCK-8) in doses of 5 or 10 micrograms/kg was injected intraperitoneally to 24 hr food-deprived rats before a 30 min feeding period, and the dopamine (DA), norepinephrine (NE) and 5-hydroxytryptamine (5-HT) contents of the hypothalamus, mesencephalon, amygdala, hippocampus and striatum were measured thereafter. The experimental procedure (deprivation + food intake) alone could induce changes in the brain monoamine contents of saline-treated animals as compared to the nondeprived control group. The most striking effect was observed in the hypothalamus, in which the contents of all three monoamines decreased. In the deprived control group there was a significant positive correlation calculated by linear regression analysis between the amount of food eaten and the DA contents of the amygdala. Injection of CCK-8 before food intake testing decreased the DA contents of the hypothalamus. In the CCK-8-treated animals the correlation between food intake and amygdaloid DA contents disappeared. The CCK-8 treatment specifically gave rise to a significant positive correlation between the amount of food eaten and the NE content of the hypothalamus; such a relation could not be observed in the saline-treated group. The hypothalamic NE contents altered in parallel with the effectiveness of both doses of CCK-8 in inhibiting food intake. The results indicate the importance of the hypothalamic NE system in the food intake-suppressing effect of CCK-8.