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The avoidance responses of mice exposed to the hot plate (55 degrees C) were found to be modified when tested a second time. In fact, when forepaws licking was no longer observed, the rearing was clearly anticipated (7 s instead of 15 s) as well as jumping (24 s instead of 55 s). These modifications of avoidance strategies as well as their latencies were still observed even 24 days after the first exposure. Avoidance responses were prevented by morphine or haloperidol injected prior to the first exposure, but not with scopolamine or diazepam. These modifications were not affected in mice injected with morphine or submitted to either a supramaximal electroshock or to ether anesthesia delivered immediately after the first hot plate exposure. Among the various known types of memory, these modifications could be linked to procedural memory.

Dopaminergic pathways play a key role in the central control of sexual behavior. Stimulation of central dopaminergic receptors elicits penile erection in a variety of species and has been proposed as a treatment option for erectile dysfunction in humans. The present study investigated the proerectile effects of apomorphine in mice. In this species, subcutaneous injection of apomorphine (range: 0.11-110 microg/kg sc) elicited three different behavioral responses: erection, erection-like responses and genital grooming. Proerectile effects of apomorphine were dose-dependent. More than 50% of mice displayed erections after administration of 1.1-11 microg/kg of apomorphine sc. Proerectile effects of apomorphine were blocked by haloperidol, a central D2 antagonist, but not by domperidone, a peripherally active dopaminergic antagonist. We conclude that apomorphine elicits erection in mice. This effect is dose-dependent and due to activation of central D2 dopaminergic receptors. The mouse model may be useful for pharmacological approaches designed to provide a better understanding of the central mechanisms of penile erection and sexual behavior.

Two lines of mice, previously selected for their sensitivity (BS) or their resistance (BR) to an anxiogenic benzodiazepine (BZ) receptor inverse agonist, methyl beta-carboline-3-carboxylate (beta-CCM), have recently been shown to present several differences in anxiety. In the present study, attempt was made to extend their behavioral profile in two situations classically used for testing antidepressant drugs. Reassessment of locomotor performance of these new populations confirmed that the motor activity of BR mice was lower than that of BS mice. In both the forced-swimming and the tail suspension tests, the immobility time of BS mice was significantly higher than that of BR mice. In the tail suspension test, two administrations of imipramine (30 mg/kg i.p., 5 h and 30 min before testing) significantly reduced the immobility time of BS mice but not of BR mice. From these data, it appears that BS mice are more "depressed" than BR mice. Thus, these selectively bred lines may represent potentially useful animal models to investigate behavioral, neurochemical and neuroendocrine correlates of antidepressant action.

Among the opioid receptors family, the cloning of the mu, kappa and delta receptors was followed by that of another member, named ORL1 (Opiate Receptor Like 1). In spite of obvious homologies with the mu, kappa and delta receptors, ORL1 does not display a relevant affinity for the endogenous ligands of these former receptors (beta endorphin, enkephalins, dynorphin A...). This observation has prompted to search for an endogenous ligand of ORL1. A heptadecapeptide which fulfils this function, with a nanomolar affinity, has been found. It was named either nociceptin or orphanin FQ. It demonstrates, according either to the dose or to the route of administration, hyperalgesic, allodynic, antiopioidergic or even analgesic effects. It displays also many behavioural effects, modifying especially locomotion, exploratory behaviour, motivation, anxiety, memory, food intake. Nociceptin results from the cleavage of a large precursor protein, prepronociceptin (PPNOC). In this latter, nociceptin is flanked on its C-terminal region by another peptide which may be regarded either as a heptadecapeptide (NocII), or a bidecapeptide (NocIII) according to the inclusion or not of a fragment constituted by 3 arginine residues. Investigating the functions modulated by NocII, we observed that it stimulates locomotor activity of mice and shortens the forepaws licking latency in the hot plate test (55 degrees C); these effects are not shared by NocIII. The simultaneous administration of NocII and nociceptin resulted in animals put on the hot plate to the appearance of their respective effects, not modified by the presence of the other. A 41 amino acid peptide flanks nociceptin on its N-terminal region in PPNOC. It may be cleaved to generate a heptadecapeptide, named nocistatin on account of its antagonist effect on the hyperalgesia/allodynia induced by nociceptin. Thus, the discovery of ORL1 has led to that of nociceptin, that of its precursor PPNOC, and thereby to that of NocII/NocIII and nocistatin. The functions modulated by these peptides are being investigated whereas their receptors are yet unknown. These multiple targets allow to expect new strategies to modulate their functions.

NocII is a heptadecapeptide whose sequence lies immediately downstream of nociceptin, the newly discovered natural agonist of the ORL1 receptor, in pronociceptin, nociceptin's precursor polypeptide. Since the sequence of NocII is framed by putative convertase excision sites and it totally conserved across murine and human species, we have sought to determine whether this orphan neuropeptide might by physiologically significant, i.e. endowed with central biological activity in vivo. Intracerebroventricular administration of 10 and 100 ng of NocII increased locomotion in mice. However, unlike nociceptin, which stimulates both the horizontal and vertical (rearing) components of locomotion, NocII affected only the horizontal component. The motor stimulant action of NocII appears to depend largely on dopamine transmission since it is totally reversed by the D1 or the D2 dopamine receptor antagonists SCH 23390 and haloperidol. NocII does not modify the number of explored holes in the hole board test, indicating that, unlike nociceptin, the orphan peptide does not affect exploratory behavior in mice.

The ORL1 receptor, an orphan receptor whose human and murine complementary DNAs have recently been characterized, structurally resembles opioid receptors and is negatively coupled with adenylate cyclase. ORL1 transcripts are particularly abundant in the central nervous system. Here we report the isolation, on the basis of its ability to inhibit the cyclase in a stable recombinant CHO(ORL1+) cell line, of a neuropeptide that resembles dynorphin A9 and whose amino acid sequence is Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln. The rat-brain cDNA encodes the peptide flanked by Lys-Arg proteolytic cleavage motifs. The synthetic heptadecapeptide potently inhibits adenylate cyclase in CHO(ORL1+) cells in culture and induces hyperalgesia when administered intracerebroventricularly to mice. Taken together, these data indicate that the newly discovered heptadecapeptide is an endogenous agonist of the ORL1 receptor and that it may be endowed with pro-nociceptive properties.

The direct D2 dopamine receptor agonist RU 24926, administered subcutaneously to mice, elicited, starting at the dose of 0.125 mg/kg, a dose dependent analgesic effect, assessed as the jump latency from a hot plate (55 degrees C). The analgesic effect induced by 0.25 mg/kg RU 24926 was dose dependently antagonized by the preferential D2 dopamine receptor antagonist haloperidol (ID50 = 15.1 +/- 3.3 micrograms/kg sc) as well as by the opioid receptor antagonist naloxone (ID50 = 0.59 +/- 0.17 mg/kg sc). The reversion of RU 24926-induced analgesia by naloxone was not accompanied by a reversion of hypothermia. Semi-chronic administration of RU 24926 (2.5 mg/kg, sc, 3 times a day for 3 days) completely desensitized to the analgesic effect induced by a 0.25 mg/kg test dose of RU 24926 and partially reduced the analgesic effect of low doses of morphine (0.5, 1, 1.5 mg/kg). Conversely, semi-chronic administration of morphine (32 mg/kg sc, twice daily for 4 days) completely desensitized the analgesic effect induced by a 2 mg/kg test dose of morphine and partially reduced the analgesic effect of RU 24926 (0.25, 0.5 and 1 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

When placed on a hot plate, rats with 5 consecutive dorsal root sections, present long licking-latencies of the posterior limbs, sign of a generalised hypoalgesia. To determine if this hypoalgesia is the result of the deafferentation or of the extent of the anterior limb automutilation performed by such deafferented rats, the licking-latency was measured in two groups of deafferented rats. In one of these groups all the rats performed automutilation, in the other a daily injection of amoxicillin resulted in an important reduction of the autotomic behavior. In both groups the licking-latency was twice its value in non-deafferented animals (order of 14 s in place of 7 s). Thus, hypoalgesia is the consequence of the deafferentation and not of the connected automutilation extent. To explain these results it is proposed that this hypoalgesia results from the algic sensitivity decrease observed in a normally afferented area when a painful sensation is felt in an other territory, the deafferented area in this case.

Ketoprofen, a non-steroidal anti-inflammatory drug, has analgesic effects in animals and humans through a peripheral as well as a central action. This study was designed to determine which brain sites are involved in the central analgesic action of ketoprofen, by using the hot-plate test. Latencies to the first hindpaw lick were recorded in animals receiving local cerebral injections of ketoprofen (10 micrograms in 0.3 microliters) or a control solution (saline). Nineteen brain sites were tested. A significant analgesia was obtained in the 8 following sites: central gray, centro-medial nucleus of the thalamus, nucleus reuniens, dorso-lateral geniculate nucleus, medial geniculate nucleus, dorso-medial and ventro-medial nuclei of the hypothalamus, posterior hypothalamic nucleus and lateral vestibular nucleus. A slight analgesia, which did not reach significance, was observed in three structures: dorsal raphé, raphé magnus and ventral postero-medial thalamic nucleus. No analgesia was observed in other sites: centro-lateral nucleus of the thalamus, posterior thalamic nuclear group, parafascicular nucleus, bed nucleus of the stria terminalis, mesencephalic tegmentum, nucleus of the tractus solitarius, spinal trigeminal complex, and brainstem reticular formation. Therefore ketoprofen seems to be centrally active mostly at the level of several integrative and non-specific structures.

The effects of 3 different non-noxious stressors on body temperature (Tb) were investigated in the rat: (1) loose restraint in cylinders, (2) removal of the rats from cylinders, exposure to a novel environment and replacement in cylinders, a stressor called here 'novelty', and (3) gentle holding of the rats by the nape of the neck. Loose restraint and 'novelty' produced hyperthermia. On the contrary, holding induced hypothermia. Hypophysectomy (HX) reduced basal Tb, abolished restraint hyperthermia and reduced both 'novelty' hyperthermia and holding hypothermia. Dexamethasone ( DEXA ) had no effect upon either restraint or novelty hyperthermia but reduced the hypothermia. Naloxone (Nx) produced a slight fall in basal Tb accounting for its reduction of restraint and 'novelty' hyperthermias ; it did not affect holding hypothermia. The inhibitory effects of HX suggest a participation of the pituitary in the hyperthermias ; the neurointermediate lobe would be involved as the hyperthermias were not affected by DEXA , which is known to block the stress-induced release of pituitary secretions from the anterior lobe but not from the neurointermediate lobe. In contrast, substances from the anterior lobe might participate in hypothermia due to holding since it is reduced by HX and DEXA . As to the effects of Nx, endogenous opioids would not be significantly involved in the thermic effects of the stressors used in this study; they might play, if any, only a minor role in the regulation of basal Tb. These results are compared with those previously obtained on nociception using the same non-noxious stressors. It emerges that, depending on the stressor, different types of association between thermoregulation and nociception may occur, i.e. hyperthermia with analgesia, hyperthermia with hyperalgesia and hypothermia with hyperalgesia.

The three neuropeptides calcitonin, neurotensin and bombesin can decrease food intake in the rat when injected into the cerebral ventricles or into the paraventricular nucleus of the hypothalamus. The paraventricular nucleus of the hypothalamus is an important site for the integration of visceral and endocrine systems, and has connections with the nucleus of the tractus solitarius which is a major locus for visceral afferents. Since calcitonin, neurotensin and bombesin, or their receptors, have been found to be present in the nucleus of the tractus solitarius, we tested the effects of local infusions of these peptides on food intake. The peptides were microinjected in a 0.25 microliter volume in rats trained to eat for only 3 hours per day. The injections were made in the rostral part of the nucleus and surrounding areas, through the lateral vestibular nuclei, to avoid leakage of the peptides into the cerebrospinal fluid. In the nucleus of the tractus solitarius the three peptides decreased food intake by more than 50%. The peptides were also active in the spinal trigeminal nucleus oralis, and, for calcitonin and bombesin, in the reticular formation under the nucleus of the tractus solitarius. A local diffusion from the point of injection may explain some of these results. Therefore, the area of the nucleus of the tractus solitarius is a nonhypothalamic site where these peptides can act to produce anorexia.

The normal level of G6PD activity of the red cells is 6.6 +/- 1.6 i.u/g Hb in men and 6.9 +/- 1.6 i.u./g Hb in women. The histogram of the distribution in the population is not symmetrical. G6PD deficiency is present in Algeria at the national level of 3% (+/- 0.5). The level is less high in the mountainous areas of arab culture, higher in the berber culture and in the Shara. Numerous new variants have been detected in Algeria. The G6PD deficiency predominating in Algeria is of Kabyle type, followed by Laghouat and El-Qued types. Types A-, A+ and Ibaden Austin of negro origin exist in the Sahara population. The Mediterranean type is not found in the Algerian population. The clinical manifestations are rare.

Unilateral section of dorsal roots C5 to T1 were performed in rats, and the automutilation behavior was measured by the extent of the limb lesions expressed in arbitrary units. Changes in the scores of automutilation were studied after the injection of four substances: a morphinomimetic (pethidine) and three antibiotics, chloramphenicol, amoxicillin, and doxycycline. Effects were tested on groups of at least eight rats that were compared with another group of eight animals operated on in the same way but injected with distilled water. The animals of the group treated with pethidine performed significantly less autotomy than did the animals in the control group. The same effect was found when the animals were injected with chloramphenicol and amoxicillin. On the contrary, doxycycline was found less efficacious. These results are discussed using the hypothesis of autotomy caused by an abnormal painful sensation felt in the deafferented forelimb.