[Behavioural studies during the gestational-lactation period in morphine treated rats]. / Viselkedési vizsgálatok a gesztációs-laktációs idoszakban morfin-kezelt patkányon.

UNLABELLED: Opioids impair the maternal behaviour of experimental animals. The effect of morphine on maternal behaviour in rat dams treated chronically with morphine during the whole pregnancy and lactation has not been yet analysed systematically. OBJECTIVE: The aim of our work was to investigate the behavioural effects of moderate dose morphine administered constantly in the whole perinatal period in rats. METHODS: Nulliparous female rats were treated with 10 mg/kg morphine s.c. once daily, from the day of mating. Maternal behaviour was observed, the effects of acute morphine treatment on the maternal behaviour and whether this effect could be antagonised by naloxone were also investigated. Physical and other behavioural (anxiety-like signals in elevated plus maze, changes in locomotor activity) withdrawal signs precipitated by naloxone were registered. After weaning sensitivity to the rewarding effect of morphine was measured by conditioned place preference and to the aversive effect of naloxone by conditioned place aversion tests. Antinociceptive test on tail-flick apparatus was performed to investigate the changes in morphine antinociceptive effects due to chronic morphine treatment. RESULTS: Maternal behaviour was significantly impaired in morphine-treated dams. This effect of morphine lasted c.a. 2-3 hours a day, it showed dose-dependency and was enhanced in MO-treated group (sensitisation). Only weak physical and no other behavioural (anxiety-like behaviour or hypolocomotion) withdrawal signs were precipitated by naloxone. The positive reinforcing effect of morphine and aversive effect of naloxone were markedly increased on conditioned place paradigm. Significant antinociceptive tolerance was not seen. CONCLUSION: Although human drug abuse can be hardly modelling under experimental circumstances, our constant, relatively moderate dose morphine treatment administered once daily during the whole pregnancy and lactation resulted in several subtle behavioural changes in dams. In perinatally opioid-exposed offspring short- and long-term behavioural disturbances can be detected which is well-known from literature. Besides direct pharmacological effects of morphine impaired maternal responsiveness and pup care could play a role in these disturbances.

Pain-inhibiting inhomogeneous static magnetic field fails to influence locomotor activity and anxiety behavior in mice: no interference between magnetic field- and morphine-treatment.

OBJECTIVES: We wanted to demonstrate (i) in the writhing test in mice, whether there was a prolonged analgesic effect induced by an inhomogeneous static magnetic field (SMF) exposure; (ii) whether SMF had an effect on the analgesic effect induced by 0.5mg/kgs.c. administered morphine, on the behavioral patterns, and on the hyperlocomotion-inducing effect of morphine. DESIGN: A magnetic exposure system developed by the present authors was used with peak-to-peak flux densities in the 2-754mT range. The writhing test was used for the assessment of pain. An elevated plus maze and a Conducta System was used for studying the anxiogenic or anxyolitic effect in mice, and the locomotor activity, respectively. OUTCOME MEASURES: We looked for the difference in the number of writhings and in the behavioral patterns between treated (s.c. morphine and/or SMF exposure) and control animals, respectively. RESULTS: (i) The antinociceptive effect could be identified 10-30min following SMF exposition in the writhing test in mice. (ii) SMF failed to affect the morphine-induced antinociception, the behavioral patterns in either type of tests, and the hyperlocomotion-inducing effect of morphine. CONCLUSIONS: (i) The long-lasting antinociceptive effect of SMF allows experiments under conditions, when in situ application of the SMF-producing device would be technically difficult or impossible; or where it would disturb the experiments. (ii) The results of behavioral tests with freely moving mice in or in the vicinity of inhomogeneous SMFs are not affected by the SMF in the applied flux density range. (iii) Morphine in treated subjects is not interacting with the inhomogeneous SMFs in the applied flux density range.

3,4-Methylenedioxymethamphetamine (MDMA), but not morphine, alters APP processing in the rat brain.

The abuse of drugs such as opioids and 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') can have detrimental effects on the cognitive functions, but the exact molecular mechanism whereby these drugs promote neurodegeneration remains to be elucidated. The major purpose of the present pilot study was to determine whether the chronic in-vivo administration of morphine (10 mg/kg) or MDMA (1 mg/kg) to rats can alter the expression and processing of amyloid precursor protein (APP), the central molecule in the proposed pathomechanism of Alzheimer's disease. MDMA treatment significantly decreased the production of APP in the cytosolic fraction of the brain cortex. A concomitant 25% increase was found both in the beta-secretase (BACE) and APP mRNA levels (108%). In contrast, in the applied single dosage chronic morphine treatment did not influence either the APP and BACE protein levels or the APP mRNA production. These results indicate that the chronic use of 'ecstasy', but not morphine, may be harmful via a novel mode of action, i.e. by altering the APP expression and processing in the brain.

The development of tolerance to locomotor effects of morphine and the effect of various opioid receptor antagonists in rats chronically treated with morphine.

Behavioural measures are considered to be highly sensitive indices of opioid withdrawal. Opioids, depending on dose and time protocols may induce both reduction and enhancement of locomotor activity and chronic opioid treatment results in tolerance and sensitisation to these effects. In the present study the locomotor activity as experimental model was used to assess the development of tolerance to subcutaneous morphine challenge at different time points following morphine withdrawal in rats exposed to gradually increasing subcutaneous doses of morphine for 11 days. Tolerance developed to the inhibitory action of morphine (10 mg/kg) was observed even 8 weeks after morphine withdrawal, while tolerance to its locomotor activity enhancing effect (3 mg/kg) was detected 18 h after withdrawal, but not 3 weeks later. In the other series of experiments the locomotor activity of animals exposed to chronic morphine treatment was tested 18 h after spontaneous or subcutaneously administrated opioid antagonists precipitated withdrawal. Spontaneous withdrawal resulted in a moderate decrease of locomotion. Both the non-selective antagonist naloxone in low, mu opioid-receptor selective doses and the delta opioid-receptor selective naltrindole induced marked reduction of locomotor activity. The results provide further evidence that both mu and delta opioid-receptors might be affected during chronic morphine treatment.

Different forms of antiparallel stacking of hydrogen-bonded antidromic rings in the solid state: polymorphism with virtually the same unit cell and two-dimensional isostructurality with alternating layers.

As a continuation of a systematic structural analysis of 2-hydroxycycloalkanecarboxylic acids and their carboxamide analogs, the effects of antidromic rings [Jeffrey & Saenger (1991). Hydrogen Bonding in Biological Structures. Berlin, Heidelberg: Springer Verlag] upon the layer stacking of cyclopentane and cycloheptane derivatives are compared. Determination of the structure of trans-2-hydroxycycloheptanecarboxylic acid (2) led to the discovery of two polymorphs with virtually the same unit cell [Kalman et al. (2003). J. Am. Chem. Soc. 125, 34-35]. (i) The layer stacking of the antidromic rings for the whole single crystal is antiparallel (2b). (ii) The antidromic rings and the 21 axis are parallel (2a), consequently the domains of the single crystal must be antiparallel. While their polymorphism is solvent-controlled, they illustrate a novel form of two-dimensional isostructurality. Antiparallel layer stacking is again demonstrated by trans-2-hydroxycycloheptanecarboxamide (3) (space group Pbca). It is built up from layers isostructural with those in the homologous trans-2-hydroxycyclopentanecarboxamide (4) [Kalman et al. (2001). Acta Cryst. B57, 539-550], but in this structure (space group Pca21) the layers are stacked in parallel mode. Similar to (2a) and (2b), the antiparallel layer stacking in (3) versus their parallel array in (4) illustrates the two-dimensional isostructurality with alternating layer orientations. Although (3) and (4) display isostructurality, they are not isomorphous.

Two polymorphs of a beta-lactam (trans-13-azabicyclo[10.2.0]tetradecan-14-one). Concomitant crystal polymorphism and isostructurality.

Two polymorphs of trans-13-azabicyclo[10.2.0]tetradecan-14-one display a unique example of isostructurality, differing only in the orientation of a given hydrogen bond with respect to the beta-lactam bond. This slight difference can be attributed to the twofold rotation of the carbocyclic macroring of C2 symmetry, which in the crystal structure is hardly noticeable.

Dipole-induced polymorphs of trans-2-hydroxycycloheptanecarboxylic acid with virtually the same unit cell.

The polymorphs of trans-2-hydroxycycloheptanecarboxylic acid have exactly the same lattice parameters and thus mimic isomorphism. They differ only in their space group: Pna21 versus Pn21a. In form II, the screw axes turn the 18-membered rings of hydrogen-bonded tetramers around the b axis. In this way, the stacking of the layers becomes antiparallel, which cancels out the dipoles within the unit cell. In form I, the same turn around the c axis leaves the stacking of the layers parallel. Thus, the dipoles are canceled out by antiparallel domains in the crystals. Between the antiparallel domains of I, each frontier is a double layer of II. This implies that (a) a pure form of I cannot be isolated and (b) the percentage of II in I may alter from crystal to crystal.

Predictable close-packing similarities between cis- and trans-2-hydroxy-1-cyclooctanecarboxylic acids and trans-2-hydroxy-1-cyclooctanecarboxamide.

In order to extend the experimental data already available on the close packing of cyclopentanes substituted with vicinal COX (X = OH, NH(2)) and OH groups to the analogous cyclohexanes, cycloheptanes and cyclooctanes, (1R*,2S*)-cis-2-hydroxy-1-cyclooctanecarboxylic acid (8C), (1R*,2R*)-trans-2-hydroxy-1-cyclooctanecarboxylic acid (8T) and (1R*,2R*)-trans-2-hydroxy-1-cyclooctanecarboxamide (8T*) were subjected to X-ray crystal structure analysis. In 8T and 8T*, the hydrogen bonds form infinite ribbons of dimers joined by R(2)(2)(12) rings with C(i) symmetry. Two types of dimer alternate along each ribbon. The dimers differ in the donor and acceptor roles of the functional groups. This pattern was previously deduced topologically among the possible forms of association for heterochiral dimers [Kálmán et al. (2002). Acta Cryst. B58, 494-501]. As they have the same pattern of hydrogen bonds, 8T and 8T* are isostructural. The additional donor (i.e. the second hydrogen of the NH(2) group) present in 8T* links the adjacent ribbons so as to form smaller R(2)(2)(8) rings between them. The crystals of the cis stereoisomer 8C are built up from antiparallel hydrogen-bonded helices. The topology and symmetry of this structure are the same as for the close packing of (1R*,2R*,4S*)-4-tert-butyl-2-hydroxy-1-cyclopentanecarboxamide [Kálmán et al. (2001). Acta Cryst. B57, 539-550]; only the hydrogen-bond donors and acceptors are interchanged, in the same way as in the two dimer types of 8T and 8T* ribbons. This analogy suggests that helices may originate as homochiral dimers with C(2) symmetry and polymerize into helices during crystal formation. The conformational characteristics of the heterochiral dimers observed in the title compounds and in closely related structures are discussed.

Novel, predicted patterns of supramolecular self-assembly, afforded by tetrameric R44(12) rings of C2 symmetry in the crystal structures of 2-hydroxy-1-cyclopentanecarboxylic acid, 2-hydroxy-1-cyclohexanecarboxylic acid and 2-hydroxy-1-cycloheptanecarboxylic acid.

Determination of the crystal structures of the homologous (1R*,2R*)-trans-2-hydroxy-1-cyclopentanecarboxylic acid (5T), (1R*,2S*)-cis-2-hydroxy-1-cyclohexanecarboxylic acid (6C) and (1R*,2S*)-cis-2-hydroxy-1-cycloheptanecarboxylic acid (7C) proved a predicted pattern of supramolecular close packing. The prediction was based on the common features observed in the crystal structures of six related 2-hydroxy-1-cyclopentanecarboxylic acids and analogous carboxamides [Kálmán et al. (2001). Acta Cryst. B57, 539-550]. This pattern is characterized by tetrameric R(4)(4)(12) rings of C(2) symmetry formed from dimeric R(2)(2)(12) rings. The C(2) symmetry of such tetramers is not common in the literature, usually they have C(i) symmetry. Both types of tetramers are formed from dimers with similar or opposite orientation. The R(2)(2)(12) dimers differ in their hydrogen bonds. In 5T the monomers are joined by a pair of O1[bond]H...O2[double bond]C bonds, whereas in 7C they are joined by a pair of O3[bond]H...O1-H bonds. In 6C 60% of the disordered R(2)(2)(12) dimers are similar to those in 7C, while 40% resemble those in 5T. Apart from these hydrogen-bonding differences and the ring-size differences, the three crystals exhibit isostructurality.