Acute antinociceptive responses in single and combinatorial opioid receptor knockout mice: distinct mu,delta and kappa tones

We have examined responses of mice lacking mu, delta and kappa opioid receptor (MOR, DOR and KOR, respectively) genes, as well as combinatorial mutants, in several pain models. This is the first truly comparative study of all three opioid receptor-deficient mice, with genotypes and gender analysis using mice on the hybrid 50% 129/SV : 50% C57BL/6 genetic background. In the tail-immersion test, only KOR-/- females showed decreased withdrawal latencies. This modification was also found in MOR/KOR and MOR/DOR/KOR, but not MOR/DOR mutants. The hotplate test revealed increased nociceptive sensitivity for MOR-/-, a phenotype which was also observed in double mutants involving the MOR deletion, and in the triple mutants. The tail-pressure test showed increased response for both MOR-/- and DOR-/- mutants, a modification which was enhanced in the triple-mutant mice. In the formalin test, MOR-/- and DOR-/- mice showed increased responses in the early and late phases, respectively, while the triple mutant tended to show enhanced nociception in both phases. Finally, the enhanced response of KOR-/- mice in the writhing test, which we have demonstrated previously, was confirmed in double MOR/KOR- and triple-mutant mice. Together, the data support the existence of an antinociceptive opioid tone. Each receptor presents a distinct pattern of activities, with mu receptors influencing responses to mechanical, chemical and thermal nociception at a supraspinal level, kappa receptors involved in spinally mediated thermal nociception and chemical visceral pain, and delta receptors modulating mechanical nociception and inflammatory pain. Phenotypes of mutant mice were subtle, suggesting a low endogenous opioid tone in the regulation of physiological pain.     

High level of mGluR7 in the presynaptic active zones of select populations of GABAergic terminals innervating interneurons in the rat hippocampus

The release of neurotransmitters is modulated by presynaptic metabotropic glutamate receptors (mGluRs), which show a highly selective expression and subcellular location in glutamatergic terminals in the hippocampus. Using immunocytochemistry, we investigated whether one of the receptors, mGluR7, whose level of expression is governed by the postsynaptic target, was present in GABAergic terminals and whether such terminals targeted particular cells. A total of 165 interneuron dendritic profiles receiving 466 synapses (82% mGluR7a-positive) were analysed. The presynaptic active zones of most GAD-(77%) or GABA-positive (94%) synaptic boutons on interneurons innervated by mGluR7a-enriched glutamatergic terminals (mGluR7a-decorated) were immunopositive for mGluR7a. GABAergic terminals on pyramidal cells and most other interneurons in str. oriens were mGluR7a-immunonegative. The mGluR7a-decorated cells were mostly somatostatin- and mGluR1alpha-immunopositive neurons in str. oriens and the alveus. Their GABAergic input mainly originated from VIP-positive terminals, 90% of which expressed high levels of mGluR7a in the presynaptic active zone. Parvalbumin-positive synaptic terminals were rare on mGluR7a-decorated cells, but on these neurons 73% of them were mGluR7a-immunopositive. Some type II synapses innervating interneurons were immunopositive for mGluR7b, as were some type I synapses. Because not all target cells of VIP-positive neurons are known it has not been possible to determine whether mGluR7 is expressed in a target-cell-specific manner in the terminals of single GABAergic cells. The activation of mGluR7 may decrease GABA release to mGluR7-decorated cells at times of high pyramidal cell activity, which elevates extracellular glutamate levels. Alternatively, the presynaptic receptor may be activated by as yet unidentified endogenous ligands released by the GABAergic terminals or the postsynaptic dendrites.     

Cellular prion protein ablation impairs behavior as a function of age

Cellular prion protein (PrPc) has been associated with some physiological functions in recent reports. Here we investigate behavioral parameters in 3- and 9-month-old mice lacking PrPc protein (Prnp0/0) and in rats after intrahippocampal administration of affinity purified anti-PrPc IgG (0.09 microg/side). No differences were observed between 3-month-old animals. However, 9-month-old Prnp0/0 mice and rats infused with anti-PrPc antibody showed a clear impairment of short- and long-term memory retention of a step-down inhibitory avoidance task. A decreased locomotor activity during exploration of an open field was also observed. These results suggest that systems involved in memory formation become more susceptible to mechanisms that require PrPc between the ages of 3 and 9 months in both mice and rats.     

Lower corneal temperature in neuroleptic-treated vs. drug-free schizophrenia patients

Antipsychotic drugs (APDs) can decrease core body temperature in schizophrenia patients. Core temperature may correlate with corneal temperature and thus, we hypothesized that neuroleptic-treated schizophrenia patients would display lower corneal temperature compared with drug-free patients. Corneal temperature of 12 typical APD-treated and 9 drug-free male schizophrenia patients was assessed using a FLIR thermal imaging camera. The APD-treated patients exhibited substantially and significantly lower corneal temperature compared with the drug-free patients (31.57 +/- 0.98 degrees C vs. 34.55 +/- 1.65 degrees C; p < 0.0001). Our results suggest that APDs may decrease corneal/core temperature in schizophrenia patients. The relevance of this finding to the pathophysiology of schizophrenia or to the antipsychotic effect of neuroleptics merit further investigation.     

Beneficial effect of donepezil augmentation for the management of comorbid schizophrenia and dementia

Comorbid schizophrenia and dementia is a common clinical phenomenon; however, management of the coexisting illnesses remains incomplete. Donepezil, a cholinesterase inhibitor, may be beneficial for the management of symptoms of Alzheimer's disease, a disease in which cholinergic pathways in the cerebral cortex and basal forebrain are well known to be compromised. Furthermore, impaired cognition in elderly schizophrenic patients has been observed to be more than two thirds; however, there are no published controlled studies reporting the use of cholinesterase inhibitors in the management of schizophrenia in patients with associated dementia. In this study, six patients with chronic schizophrenia and comorbid dementia were administered donepezil, 5 mg, in single-blind fashion as augmentation to their standard antipsychotic medication for a 4-week period. Patients were evaluated with the Mini Mental State Examination (MMSE); Alzheimer's Disease Assessment Scale, Cognitive subscale; Positive and Negative Symptom Scale (PANSS); and the Clinical Global Impression (CGI) scales. A significant improvement was noted in MMSE scores (P < 0.01) and for CGI scores (P < 0.01). In addition, three patients demonstrated improvement on the PANSS. Donepezil appears to be an effective treatment for the management of symptoms of dementia accompanying patients with comorbid schizophrenia and dementia. Since cholinergic dysfunction may be present in some patients with schizophrenia, the authors' findings further demonstrate the possibility that this disorder may be managed with cholinergic medications as augmenting agents, at least in this specific subpopulation of patients with comorbid dementia. To confirm the findings of this preliminary trial, further investigation is mandated with a larger sample of subjects in the context of a double-blind medication trial.     

Alteration of CCK-induced satiety in post-Nippostrongylus brasiliensis-infected rats

In rats, the nematode Nippostrongylus brasiliensis induces an intestinal inflammation, but after the inflammation had resolved and the worm burden eliminated, morphological alterations of the intestinal wall, mainly consisting of mast cell hyperplasia and enteric nerve remodeling, persist for several weeks. Intestinal signals reaching the brain through the vagus nerve and involving neuropeptides such as CCK, play a role in the control of food intake. Our hypothesis was that neuroimmune alterations of the intestine may alter this control. This work was aimed to evaluate whether post-infection alterations of the intestinal wall may affect the satiety effects of CCK and further, the role of mast cells and their mediators, histamine and serotonin, in post-N. brasiliensis-infected rats. In basal conditions, food intake was not different in control and post-infected groups of rats. Post-infected rats were characterized by prolonged satiety effects of both CCK and histamine but not serotonin. The prolonged effect of CCK was reduced when mast cells were previously stabilized by ketotifen, which had no effect per se on food intake. No difference was observed in the increase of food intake induced by CCK-A and CCK-B receptor antagonists in both control and post-infected rats. Mast cell degranulation with compound 48/80 induced severe anorectic effects that lasted for less than 24h in post-infected rats and as long as 6 days in controls. Thus, in our experimental conditions, i.e., within 30-50 days post-N. brasiliensis infection, we observed an enhancement of the anorectic effect of exogenous CCK involving mast cell degranulation and histamine.     

Prevention of dental caries in partially erupted permanent teeth with a CO2 laser

OBJECTIVE: The purpose of this study was to determine the effect of CO2 laser irradiation in the prevention of pit and fissure caries in immature molars with covering opercula. BACKGROUND DATA: In pediatric dentistry, it is not unusual to find partially erupted immature permanent teeth, especially with opercula. Conventional dental caries prevention is not effective in these cases because of the immaturity of tooth substance and the presence of the opercula, which accumulate a substantial amount of plaque. MATERIALS AND METHODS: The CO2 laser was used on 22 immature erupting molars with opercula. In each case, we first cut the operculum with a CO2 laser in a 2- or 3-watt continuous mode. Then, the occlusal surface was irradiated spot by spot along the pits and fissures of the molar using a CO2 laser in a 2-watt pulsed mode with 0.2 sec of irradiation time (average power, 0.3 watt; pulse width, 10 msec; repetition time, 15 Hz; energy density, 15 J/cm2). Each of the studied teeth was clinically examined for dental caries for 3 years. RESULTS: It took less than 2 min to cut the operculum, and there was no bleeding. The irradiation imparted acid resistance to the teeth without any discomfort to the patients. The patients did not complain of any pain after the procedure. Only two of the studied teeth developed dental caries during the observation period. CONCLUSION: We conclude that a CO2 laser might be an effective mode of treatment in the prevention of pit and fissure caries in partially erupted permanent molars covered with opercula.     

Clinical evaluation of the Elecsys CA 15-3 test in breast cancer patients

The aim of the present study was to evaluate the clinical performance of the CA 15-3 assay on Elecsys systems in an international multicenter study (11 centers). A total of 1326 single samples (272 apparently healthy individuals, 34 pregnant women, 308 benign diseases, 273 cancers other than breast, 439 breast cancer) and 538 serial samples of 98 breast cancer patients during follow-up were analyzed. 95% of values in healthy individuals were below 25 kU/L, and 88% in benign breast diseases, respectively. In malignant breast disease at primary diagnosis the value distribution of Elecsys CA 15-3, sensitivity at 95% specificity, as well as the areas under the curve in ROC analysis were clearly correlated to tumor stages: UICC I to IV 88 to 25% of values < 25 kU/L, sensitivity 7 to 78%, areas under the curve 0.53 to 0.94. During follow-up, sensitivity/specificity for detection of recurrences were 90%/71%. In metastatic disease clinical progression/response to therapy were indicated in 91%/78% of patients at a specificity of 92%/78%. The findings indicate that the Elecsys CA 15-3 assay is very suitable in routine work for detection of recurrences as well as for therapy control in metastatic breast cancer.     

Intratympanic gentamicin for intractable Meniere's disease

OBJECTIVE: The study aimed to analyze the results of the intratympanic injection of gentamicin as a treatment option for patients with unilateral Meniere's disease who were refractory to medical treatment. STUDY DESIGN: Prospective study in the setting of a tertiary care medical center. METHODS: Seventy-one patients with unilateral Meniere's disease according to 1995 American Academy of Otolaryngology-Head and Neck Surgery 1995 guidelines who had been unresponsive to medical therapy for at least 1 year were studied. Intratympanic injections of a prepared concentration of 27 mg/mL gentamicin were performed at weekly intervals until the development of symptoms and signs indicative of vestibular hypofunction in the treated ear. As the main outcome measure, the 1995 American Academy of Otolaryngology-Head and Neck Surgery criteria for reporting treatment outcome in Meniere's disease were used. The results of treatment were expressed in terms of control of vertigo, disability status (functional level and degree of overall impairment evaluated by the Dizziness Handicap Inventory and the University of California Los Angeles Dizziness Questionnaire), hearing level, and quantitative measurement of vestibular function. RESULTS: Vertigo was controlled in 83.1% of the 71 patients. Recurrence of vertigo spells after initially complete control was noted in 17 patients. In 13 of these patients, this was cured by another course of intratympanic injections of gentamicin. Functional level and measures of self-reported handicap were significantly and promptly lowered after treatment in the patients who attained control of vertigo. Hearing level as pure-tone average was unchanged 2 years after treatment, but hearing loss as a result of gentamicin injections occurred in 23 patients at the end of treatment and in 9 and 11 patients at 3 months and 2 years after the treatment, respectively. Vestibular function was kept normal or reduced in 49.3% of the patients, whereas in the rest of the patients vestibular areflexia was observed. Control of vertigo did not depend on the amount of vestibular damage. CONCLUSIONS: Ending weekly intratympanic injections when clinical signs of vestibular deafferentation appear can control vertigo in the majority of patients, and it is a useful alternative, together with other surgical options, for the treatment of patients with Meniere's disease who do not respond to medical treatment.