Decreased motivational properties of morphine in mouse models of cancerous- or inflammatory-chronic pain: implication of supraspinal neuropeptide FF(2) receptors.

Our main purpose was to evaluate the influence of cancer pain on the rewarding properties of morphine. Opioids are very addictive when used by healthy persons, conversely the occurrence of an opioid addiction seems very low when patients suffering from cancer are treated with morphine. We investigated the reinforcing properties of morphine in the place preference paradigm on a new model of mice suffering from a cancer pain induced by syngenic melanoma cells injected in the hind paw. These data were compared with mice suffering either from a short-term- or a chronic-inflammatory pain induced respectively by injection of carrageenan or complete Freund's adjuvant. Remarkably, mice suffering from cancer pain or chronic inflammatory pain did not develop any preference for the environment associated with the injection of morphine. In mice injected with melanoma cells, the specific binding of [(125)I]EYWSLAAPQRF-NH(2), an agonist of neuropeptide FF(2) receptors, was increased in several brain areas involved in the rewarding properties of opiates, including the shell of the nucleus accumbens, the major islands of Calleja, the ventral endopiriform nucleus and the amygdaloid area. Our study is the first to reveal a modification of morphine rewarding properties under cancer pain in rodents. We postulate that anti-opioid neuropeptides might contribute to the suppression of morphine rewarding effects in this murine model of cancer pain.

Two QTLs located on chromosomes 1 and 5 modulate different aspects of the performance of mice of the B x D Ty RI strain series in the Morris navigation task.

The Morris navigation task is widely used to study spatial abilities in rodents; namely, to analyze the effects of mutations in genetically engineered mice. Although quantitative and Mendelian genetic studies have shown that the variation of these abilities is partly under genetic control, little is known about these genetic factors. In order to analyze the genetic architecture of spatial navigation in mice, a wide genome scan was performed to map the QTLs that control various aspects of the performance, using the RI strain methodology. Latencies to locate the submerged platform across learning sessions and performance to the spatial probe test were analyzed in the 26 strains of the B x D RI series. Both cluster analysis of behavioral measurements and QTL mapping confirmed previous data showing that the escape latencies and the spatial bias rely on two distinct components of the task, controlled by different loci. A QTL on chromosome 1 influenced escape latencies during the four training sessions, whereas another QTL, located on chromosome 5, was shown to control spatial performance at the probe trial and also exhibited epistatic interactions with two other QTLs on chromosomes 2 and 13. The function of these QTLs is examined in the broader context of hippocampal-dependent learning processes and in relation to QTLs already found in similar positions in other behavioral traits.

Approaches to drug therapy, formulary, and pathway management in a large community hospital.

Use of a clinical pathway for the management of community-acquired pneumonia (CAP) at a large community hospital is described. The pathway was developed and implemented by a multidisciplinary team. Fluoroquinolone therapeutic interchange and intravenous (i.v.) to oral (p.o.) conversion were part of the pathway; through literature review, levofloxacin was chosen as the preferred quinolone. Outcomes (length of stay [LOS] and readmission rates for pathway and nonpathway patients with CAP, economic impact of the fluoroquinolone interchange protocol, and resistance patterns) were evaluated. For pathway patients in 1998, LOS was 1.2 days shorter and the readmission rate was lower. Projected drug cost savings as a result of the fluoroquinolone interchange protocol were more than $22,000 annually. Pharmacists' interventions in antimicrobial prescribing for CAP patients can lead to cost efficiency and positively affect patient outcomes.

Behavioral alterations associated with apoptosis and down-regulation of presenilin 1 in the brains of p53-deficient mice.

Presenilin 1 (PS1) expression is repressed by the p53 tumor suppressor. As shown herein, wild-type PS1 is an effective antiapoptotic molecule capable of significantly inhibiting p53-dependent and p53-independent cell death. We analyzed, at the functional and molecular levels, the brains of p53 knockout mice. Surprisingly, we found that lack of p53 expression induces apoptotic brain lesions, accompanied by learning deficiency and behavioral alterations. p53-deficient mice show an unexpected overexpression of p21(waf1) with subsequent down-regulation of PS1 in their brains. This process is progressive and age-dependent. These data indicate that the p53 pathway, besides affecting tumor suppression, may play a major role in regulating neurobehavioral function and cell survival in the brain.

Reversible inactivation of the hippocampal mossy fiber synapses in mice impairs spatial learning, but neither consolidation nor memory retrieval, in the Morris navigation task.

The role played by hippocampal mossy fibers in the learning and memory processes implemented in the Morris swimming navigation task has been studied in C57BL/6 mice by selective and reversible inactivation of mossy fiber synaptic fields by diethyldithiocarbamate. The functional integrity of the mossy fibers proved essential for the storage of the spatial representation on the modifiable synapses of the recurrent collaterals of the CA3 pyramidal cells, whereas it is not necessary for the consolidation and recall of spatial memories. The results suggest that mossy fibers are preferentially involved in new learning. They are consistent with the hypothesis that the hippocampal CA3 region might act as an autoassociation memory.

Analysis of behavioral and hippocampal variation in congenic albino and pigmented BALB mice.

Mice of the BALB/c strain are widely used in behavioral research in spite of the albino condition, which can obscure brain-behavior relationships. We have developed a pigmented BALB strain, congenic to BALB/c, which could be more appropriate for neurogenetic studies that aim at identifying the effects of neurological mutations on behavior. Comparison of inbred albino and pigmented congenic BALB arising from the same litters provides a valuable tool for detecting the consequences of the albino mutation on behavioral performances. Preliminary results presented here show that the albino condition does not interfere with the development and patterns of connectivity of mossy fibers in the hippocampus. On the other hand, obvious coat color-linked differences appear for locomotor activity and defecation scores in the open field, pigmented mice being unexpectedly less active and more reactive than albino, as if better vision increased their reactions to a novel, anxiogenic environment. Finally, pigmented mice do not show better performances in the radial maze, which confirms that the inability of BALB mice for spatial learning in a highly demanding version of this task cannot be attributed to their inability to process visual information.

Morphological and biochemical confirmation of gray platelet syndrome in two siblings.

A case report is presented of gray platelet syndrome in siblings. The absence of platelet alpha-granules in these patients was confirmed by electron microscopy and by analysis of the platelet protein profile using SDS-polyacrylamide gel electrophoresis. This was further confirmed by quantitation of individual alpha-granule protein constituents. The results in these two patients are compared with those of the four reported patients with this syndrome.