[Pain and analgesia : Mutations of voltage-gated sodium channels]. / Schmerz und Schmerzlosigkeit : Mutationen spannungsabhängiger Natriumkanäle.

Voltage-gated sodium channels (Navs) are crucial for the generation and propagation of action potentials in all excitable cells, and therefore for the function of sensory neurons as well. Preclinical research over the past 20 years identified three Nav-isoforms in sensory neurons, namely Nav1.7, Nav1.8 and Nav1.9. A specific role for the function of nociceptive neurons was postulated for each. Whereas no selective sodium channel inhibitors have been established in the clinic so far, the relevance of all three isoforms regarding the pain sensitivity in humans is currently undergoing a remarkable verification through the translation of preclinical data into clinically manifest pictures. For the last ten years, Nav1.7 has been the main focus of clinical interest, as a large number of hereditary mutants were identified. The so-called "gain-of-function" mutations of Nav1.7 cause the pain syndromes hereditary erythromelalgia and paroxysmal extreme pain disorder. In addition, several Nav1.7 mutants were shown to be associated with small-fiber neuropathies. On the contrary, "loss-of-function" Nav1.7 mutants lead to a congenital insensitivity to pain. Recently, several gain-of-function mutations in Nav1.8 and Nav1.9 have been identified in patients suffering from painful peripheral neuropathies. However, another gain-of-function Nav1.9 mutation is associated with congenital insensitivity to pain. This review offers an overview of published work on painful Nav mutations with clinical relevance, and proposes possible consequences for the therapy of different pain symptoms resulting from these findings.

Group versus individual reinforcement contingencies within the context of group study conditions.

We investigated the effects of two teaching variables on students' Spanish vocabulary quiz performance: (a) group study and (b) individual versus group contingencies. In Experiment 1, we compared students' quiz scores under conditions in which students either studied independently and received no programmed reinforcement or studied in groups and received individual rewards for high scores. The results showed that, on average, the group-study individual-reward condition produced superior quiz scores. In Experiment 2, we compared individual (i.e., the superior condition in Experiment 1) and group contingencies within the context of the group study condition. On average across the class, group contingencies produced performance superior to individual contingencies. In both studies, however, benefits for the classes as a whole were mitigated by effects on individual students. These results extend the literature on the effects of group-based instructional activities and reinforcement contingencies. Educators who choose such procedures may encounter conflicting findings depending on whether they examine results at the group or individual level.

Long-term effects of lactational zinc deficiency on bone mineral composition in rats fed a commercially modified Luecke diet.

The purpose of this study was threefold: 1. to determine the long-term effects of interactions between lactational zinc deficiency and gender on bone mineral composition in repleted rat offspring, 2. to determine the nutritional efficacy of the second of two commercially designed, modified Luecke diets (ML2) during the gestational and lactational stress, and 3. determine the ultratrace element contents of Ralston Rodent Laboratory Chow #5001. The ML2 basal diet, based on dextrose, sprayed egg white, and corn oil contained 0.420 micrograms Zn/g, was supplemented with Zn (as zinc acetate) at 0 (diet 0ML2) or 30 (diet 30ML2) micrograms/g, and was mixed and pelleted commercially. All rat dams were fed the 30ML2 diet ad libitum during gestation. Beginning at parturition, the dams were fed either the 1. 0ML2, 2. 30ML2 (food restricted), or 3. 30ML2 (ad libitum) diets. All pups were fed the 30ML2 diet ad libitum from 23 to 40 d of age. From d 40 to 150, all pups were fed Ralston Rodent Laboratory Chow. The 30ML2 diet was found to be nutritionally efficacious; litter size and pup growth were normal and pup mortality was only 1.2%. Pups (ZD) with access to the 0ML2 diet until 23 d of age and nursed by dams fed the 0ML2 diet, when compared to pups (PF) fed restricted amounts of the 30ML2 diet, exhibited increased mortality and decreased concentrations of tibial zinc but no change in growth. Inadequate zinc nutriture during infancy, despite postlactational zinc repletion, induced imbalances in adult bone mineral metabolism. Thus, at 150 d of age, the ZD pups exhibited increased levels of bone P and Mg and decreased concentrations of K as compared to the PF pups.

Developmental delays in offspring of rats undernourished or zinc deprived during lactation.

Offspring of rats who were zinc or calorie deprived during lactation were administered a battery of reflex and motor tests from postnatal Day 4 to Day 21. Compared to offspring of ad lib-fed control rats, both zinc deprived and undernourished offspring exhibited developmental delays in reflexes which appeared after the first postnatal week (auditory startle, air righting, and rope descent). As the deficiencies continued the delays appeared to be more pronounced. The zinc deficiency did not add to the deficits associated with calorie restriction alone because there were no significant differences between the zinc deficient and undernourished pups on any of the measures except eye opening. When rehabilitated offspring were tested at 45 and 60 days of age for motor deficits there were no significant impairments resulting from preweaning dietary conditions. However, the growth retardation of zinc deprived and undernourished rats persisted long after dietary rehabilitation was implemented.

Learning and memory disabilities in young adult rats from mildly zinc deficient dams.

Three experiments were conducted to test the behavior of the offspring of rat dams (ZD) fed a mildly zinc deficient diet (10.0 micrograms Zn/g) during pregnancy and lactation. Since zinc deficiency causes anorexia, a second group of rat dams (PF) was fed the same quantity of the diet during gestation and lactation as was consumed by their ZD mates. A third group of rats (AL) was fed the diet ad lib during gestation and lactation. The PF and AL dams were given zinc supplemented (25.0 micrograms Zn/ml) drinking water whereas the ZD dams were given double distilled, deionized drinking water. After weaning, the offspring of all dams were fed Purina Laboratory Chow ad lib until they were 100 days old. The offspring were then reduced to 85% of their ad lib weight and tested on a 17-arm radial maze for memory and learning. In Experiments 1 and 2, the ZD males suffered a significant learning deficit when compared to the AL males. Whereas the PF males suffered a significant learning impairment in Experiment 1, the learning deficit of the PF group was not as severe as the deficit of the ZD group. There was no impairment in reference (long-term) memory for any of the groups. In Experiment 3, significant differences in working (short-term) memory were found among the three groups of females. The ZD group was significantly inferior in working memory when compared to the PF and AL groups. No significant differences in working memory were found between the PF and AL groups.

Learning and memory impairment in adult rats due to severe zinc deficiency during lactation.

In a series of three experiments, adult rats who suffered severe zinc deficiency and/or undernutrition during lactation were tested in a 17-arm radial maze for working memory, reference memory, forgetting and learning. In Experiment 1, eight out of 17 arms were baited. The zinc deficient (ZD) and undernourished (PF) rats revealed a learning deficit when compared to adequately nourished rats (AL). ZD rats also appeared to display a loss of working memory. No evidence of loss of reference memory was observed among any of the groups. A reverse learning procedure was used in Experiment 2 to test the same rats used in Experiment 1. ZD rats were significantly inferior in performance of the reverse learning task compared to the AL and PF rats. No significant differences in performance were noted between the AL and PF rats. Although all groups displayed forgetfulness from Experiment 1 to Experiment 2, no significant differences in forgetfulness were evidenced among the groups. In Experiment 3, all 17 arms were baited. The ZD rats displayed a significant working memory deficit as compared to the AL and PF rats. No significant differences in working memory between the AL and PF rats occurred. The possibility that the differences in performance were due to differences in food motivation or attention was considered and rejected. It was concluded that ZD rats experienced a severe learning deficit and some working memory deficit while the PF rats experienced a mild learning deficit as compared to the AL rats.