Biosynthesis of neuroprotective melatonin is dysregulated in Huntington's disease.

Huntington's disease (HD) is a progressive neurodegenerative brain disorder associated with uncontrolled body movements, cognitive decline, and reduced circulating melatonin levels. Melatonin is a potent antioxidant and exogenous melatonin treatment is neuroprotective in experimental HD models. In neurons, melatonin is exclusively synthesized in the mitochondrial matrix. Thus, we investigated the integrity of melatonin biosynthesis pathways in pineal and extrapineal brain areas in human HD brain samples, in the R6/2 mouse model of HD and in full-length mutant huntingtin knock-in cells. Aralkylamine N-acetyltransferase (AANAT) is the rate-limiting step enzyme in the melatonin biosynthetic pathway. We found that AANAT expression is significantly decreased in the pineal gland and the striatum of HD patients compared to normal controls. In the R6/2 mouse forebrain, AANAT protein expression was decreased in synaptosomal, but not nonsynaptosomal, mitochondria and was associated with decreased synaptosomal melatonin levels compared to wild type mice. We also demonstrate sequestration of AANAT in mutant-huntingtin protein aggregates likely resulting in decreased AANAT bioavailability. Paradoxically, AANAT mRNA expression is increased in tissues where AANAT protein expression is decreased, suggesting a potential feedback loop that is, ultimately unsuccessful. In conclusion, we demonstrate that pineal, extrapineal, and synaptosomal melatonin levels are compromised in the brains of HD patients and R6/2 mice due, at least in part, to protein aggregation.

The SCFFBXO3 ubiquitin E3 ligase regulates inflammation in atherosclerosis.

Inflammation is critical in the pathobiology of atherosclerosis. An essential player in the inflammatory process in atherosclerosis are macrophages that scavenge oxidatively modified low-density lipoproteins (OxLDL) deposited in the subendothelium of systemic arteries that secrete a myriad of pro-inflammatory mediators. Here, we identified that a subunit of the Skp-Cullin-F-box ubiquitin E3 ligase apparatus, termed FBXO3, modulates the inflammatory response in atherosclerosis. Specifically, individuals with a hypofunctioning genetic variant of FBXO3 develop less atherosclerosis. FBXO3 protein is present in cells of monocytic lineage within carotid plaques and its levels increase in those with symptomatic compared with asymptomatic atherosclerosis. Further, cellular depletion or small molecule inhibition of FBXO3 significantly reduced the inflammatory response to OxLDL by macrophages without altering OxLDL uptake. Thus, FBXO3 potentiates vascular inflammation and atherosclerosis that can be effectively mitigated by a small molecule inhibitor.

Regional Molecular Signature of the Symptomatic Atherosclerotic Carotid Plaque.

BACKGROUND: Many studies have explored molecular markers of carotid plaque development and vulnerability to rupture, usually having examined whole carotid plaques. However, there are regional differences in plaque morphology and known shear-related mechanisms in areas surrounding the lipid core. OBJECTIVE: To determine whether there are regional differences in protein expression along the long axis of the carotid plaque and how that might produce gaps in our understanding of the carotid plaque molecular signature. METHODS: Levels of 7 inflammatory cytokines (IL-1ß, IL-6, IL-8, IL-10, IL-12 p70, IFN-γ, and TNF-α) and caspase-3 were analyzed in prebifurcation, bifurcation, and postbifurcation segments of internal carotid plaques surgically removed from symptomatic and asymptomatic patients. Expression profiles of miRNAs and mRNAs were determined with microarrays for the rupture-prone postbifurcation segment for comparison with published whole plaque results. RESULTS: Expression levels of all proteins examined, except IL-10, were lowest in the prebifurcation segment and significantly higher in the postbifurcation segment. Patient group differences in protein expression were observed for the prebifurcation segment; however, no significant differences were observed in the postbifurcation segment between symptomatic and asymptomatic patients. Expression profiles from postbifurcation carotid plaques identified 4 novel high priority miRNAs differentially expressed between patient groups (miR-214, miR-484, miR-942, and miR-1287) and 3 high-confidence miRNA:mRNA targets, including miR-214:APOD, miR-484:DACH1, and miR-942:GPR56. CONCLUSION: The results demonstrate regional differences in protein expression for the first time and show that focus on the rupture-prone postbifurcation region leads to prioritization for further study of novel miRNA gene regulation mechanisms.

Observations from Social Media Regarding the Symptomatology of Adult Hydrocephalus Patients.

BACKGROUND: Patients with hydrocephalus experience symptoms related to hydrocephalus in an age-dependent manner. However, prevalence estimates of hydrocephalus symptoms in young and middle-aged (YMA) adult patients are rare and variable. Highlighting the importance of hydrocephalus symptom management, the persistence and intensity of headache or gait disturbance have been associated with signs of brain white matter integrity loss, including in treated YMA adult patients. Thus, it is important to ascertain which symptoms adult patients with hydrocephalus report most to confirm their relative importance. METHODS: Observations of symptom complaints were made from publicly viewable online responses to an inquiry posted by the Hydrocephalus Association to 2 Facebook webpages. RESULTS: Within 7 days of inquiry posting, 381 complaints of signs and symptoms were identified in 82 online responses. Headache, cognitive deficits (cognition and memory), and mobility issues (dizziness, balance, or gait problems) were most commonly reported by 63%, 45%, and 40% of respondents, respectively. Results were highly similar for the subgroup of 53 patients reported as treated. For self-identified YMA patients (<60 years old), results were similar, but with fewer mobility complaints. Not previously reported, hypersensitivity to external stimuli was reported by one-half of the patients that reported headache. CONCLUSIONS: The current results provide further quantitative support for the prioritization of study of headache, cognitive deficits, and mobility issues in YMA adult patients with hydrocephalus. Warranting further study, cranial hypersensitivity to external stimuli may represent a novel outcome measure, and treated YMA adult hydrocephalus patients continue to report symptoms associated with signs of brain damage.

Comparative durability and costs analysis of ventricular shunts.

OBJECTIVE: Ventricular shunt (VS) durability has been well studied in the pediatric population and in patients with normal pressure hydrocephalus; however, further evaluation in a more heterogeneous adult population is needed. This study aims to evaluate the effect of diagnosis and valve type-fixed versus programmable-on shunt durability and cost for placement of shunts in adult patients. METHODS: The authors retrospectively reviewed the medical records of all patients who underwent implantation of a VS for hydrocephalus at their institution over a 3-year period between August 2013 and October 2016 with a minimum postoperative follow-up of 6 months. The primary outcome was shunt revision, which was defined as reoperation for any indication after the initial procedure. Supply costs, shunt durability, and hydrocephalus etiologies were compared between fixed and programmable valves. RESULTS: A total of 417 patients underwent shunt placement during the index time frame, consisting of 62 fixed shunts (15%) and 355 programmable shunts (85%). The mean follow-up was 30 ± 12 (SD) months. The shunt revision rate was 22% for programmable pressure valves and 21% for fixed pressure valves (HR 1.1 [95% CI 0.6-1.8]). Shunt complications, such as valve failure, infection, and overdrainage, occurred with similar frequency across valve types. Kaplan-Meier survival curve analysis showed no difference in durability between fixed (mean 39 months) and programmable (mean 40 months) shunts (p = 0.980, log-rank test). The median shunt supply cost per index case and accounting for subsequent revisions was $3438 (interquartile range $2938-$3876) and $1504 (interquartile range $753-$1584) for programmable and fixed shunts, respectively (p < 0.001, Wilcoxon rank-sum test). Of all hydrocephalus etiologies, pseudotumor cerebri (HR 1.9 [95% CI 1.2-3.1]) and previous shunt malfunction (HR 1.8 [95% CI 1.2-2.7]) were found to significantly increase the risk of shunt revision. Within each diagnosis, there were no significant differences in revision rates between shunts with a fixed valve and shunts with a programmable valve. CONCLUSIONS: Long-term shunt revision rates are similar for fixed and programmable shunt pressure valves in adult patients. Hydrocephalus etiology may play a significant role in predicting shunt revision, although programmable valves incur higher supply costs regardless of initial diagnosis. Utilization of fixed pressure valves versus programmable pressure valves may reduce supply costs while maintaining similar revision rates. Given the importance of developing cost-effective management protocols, this study highlights the critical need for large-scale prospective observational studies and randomized clinical trials of ventricular shunt valve revisions and additional patient-centered outcomes.

Imputation of Truncated p-Values For Meta-Analysis Methods and Its Genomic Application.

Microarray analysis to monitor expression activities in thousands of genes simultaneously has become routine in biomedical research during the past decade. a tremendous amount of expression profiles are generated and stored in the public domain and information integration by meta-analysis to detect differentially expressed (DE) genes has become popular to obtain increased statistical power and validated findings. Methods that aggregate transformed p-value evidence have been widely used in genomic settings, among which Fisher's and Stouffer's methods are the most popular ones. In practice, raw data and p-values of DE evidence are often not available in genomic studies that are to be combined. Instead, only the detected DE gene lists under a certain p-value threshold (e.g., DE genes with p-value < 0.001) are reported in journal publications. The truncated p-value information makes the aforementioned meta-analysis methods inapplicable and researchers are forced to apply a less efficient vote counting method or naïvely drop the studies with incomplete information. The purpose of this paper is to develop effective meta-analysis methods for such situations with partially censored p-values. We developed and compared three imputation methods-mean imputation, single random imputation and multiple imputation-for a general class of evidence aggregation methods of which Fisher's and Stouffer's methods are special examples. The null distribution of each method was analytically derived and subsequent inference and genomic analysis frameworks were established. Simulations were performed to investigate the type Ierror, power and the control of false discovery rate (FDR) for (correlated) gene expression data. The proposed methods were applied to several genomic applications in colorectal cancer, pain and liquid association analysis of major depressive disorder (MDD). The results showed that imputation methods outperformed existing naïve approaches. Mean imputation and multiple imputation methods performed the best and are recommended for future applications.

Nanoanesthesia: a novel, intravenous approach to ankle block in the rat by magnet-directed concentration of ropivacaine-associated nanoparticles.

BACKGROUND: As an alternative to current methods of local nerve block, we studied the feasibility of producing ankle block in the rat with IV injection of magnetic nanoparticles (MNPs) associated with ropivacaine and application of a magnet at the ankle. METHODS: The anesthetic effect of magnet-directed ropivacaine-associated MNPs (MNP/Ropiv) was tested in the rat using paw withdrawal latencies from thermal stimuli applied to the hindpaw. The MNP/Ropiv complexes consisted of 0.7% w/v ropivacaine and 0.8% w/v MNPs containing 12% w/w magnetite (F3O4). The effect of IV injection of MNP/Ropiv with 15, 30, and 60-minute magnet application to the right ankle was compared with the effect without magnet application on the left hindpaw, to conventional ankle block with 0.1% or 0.2% ropivacaine, and to IV injection of MNPs alone with 30-minute magnet application to the right ankle. In addition, the pharmacokinetics of the MNP/Ropiv complexes were determined. RESULTS: IV injection of MNP/Ropiv with magnet application at the ankle significantly increased paw withdrawal latencies from thermal stimuli compared with pretreatment baselines in the same paw (P < 0.0001) and compared with the contralateral paw without magnet application (P < 0.0001). IV injection of MNPs alone had no significant effect on paw withdrawal latency. Absolute ropivacaine concentrations in ankle tissue, and ankle tissue-to-plasma concentration ratios were higher in the MNP/Ropiv group with 30-minute magnet application compared with MNP/Ropiv group without magnet application (mean ± SEM, 150 ± 10 ng/g vs 105 ± 15 ng/g, respectively, and 6.1 ± 0.8 vs 4.2 ± 0.7, respectively). CONCLUSIONS: The current study establishes proof of principle that it is possible to produce ankle block in the rat by IV injection of MNP/Ropiv complexes and magnet application at the ankle. The results indicate that further study of this approach is warranted.

Heritability of nociception IV: neuropathic pain assays are genetically distinct across methods of peripheral nerve injury.

Prior genetic correlation analysis of 22 heritable behavioral measures of nociception and hypersensitivity in the mouse identified 5 genetically distinct pain types. In the present study, we reanalyzed that dataset and included the results of an additional 9 assays of nociception and hypersensitivity, with the following goals: to replicate the previously identified 5 pain types; to test whether any of the newly added pain assays represent novel genetically distinct pain types; and to test the level of genetic relatedness among 9 commonly used neuropathic pain assays. Multivariate analysis of pairwise correlations between assays shows that the newly added zymosan-induced heat hypersensitivity assay does not conform to the 2 previously identified groups of heat hypersensitivity assays and cyclophosphamide-induced cystitis, the first organ-specific visceral pain model examined, is genetically distinct from other inflammatory assays. The 4 included mechanical hypersensitivity assays are genetically distinct and do not comprise a single pain type as previously reported. Among the 9 neuropathic pain assays including autotomy, chemotherapy, nerve ligation and spared nerve injury assays, at least 4 genetically distinct types of neuropathic sensory abnormalities were identified, corresponding to differences in nerve injury method. In addition, 2 itch assays and Comt genotype were compared to the expanded set of nociception and hypersensitivity assays. Comt genotype was strongly related only to spontaneous inflammatory nociception assays. These results indicate the priority for continued investigation of genetic mechanisms in several assays newly identified to represent genetically distinct pain types.

Pain modality- and sex-specific effects of COMT genetic functional variants.

The enzyme catechol-O-methyltransferase (COMT) metabolizes catecholamine neurotransmitters involved in a number of physiological functions, including pain perception. Both human and mouse COMT genes possess functional polymorphisms contributing to interindividual variability in pain phenotypes such as sensitivity to noxious stimuli, severity of clinical pain, and response to pain treatment. In this study, we found that the effects of Comt functional variation in mice are modality specific. Spontaneous inflammatory nociception and thermal nociception behaviors were correlated the most with the presence of the B2 SINE transposon insertion residing in the 3'UTR mRNA region. Similarly, in humans, COMT functional haplotypes were associated with thermal pain perception and with capsaicin-induced pain. Furthermore, COMT genetic variations contributed to pain behaviors in mice and pain ratings in humans in a sex-specific manner. The ancestral Comt variant, without a B2 SINE insertion, was more strongly associated with sensitivity to capsaicin in female vs male mice. In humans, the haplotype coding for low COMT activity increased capsaicin-induced pain perception in women, but not men. These findings reemphasize the fundamental contribution of COMT to pain processes, and provide a fine-grained resolution of this contribution at the genetic level that can be used to guide future studies in the area of pain genetics.

The associations between OPRM 1 and COMT genotypes and postoperative pain, opioid use, and opioid-induced sedation.

Previous studies have associated mu-opioid receptor (OPRM1) genotype with pain and analgesia responses in postoperative and patient populations. This study investigates the role of catechol-O-methyltransferase (COMT) and OPRM1 genotypes in acute postoperative pain scores, opioid use, and opioid-induced sedation after surgical procedures for orthopedic trauma in an otherwise healthy patient population. Verbal pain/sedation scores, opioid use, and physiologic responses in the immediate postoperative period were examined for association with genetic variants in Caucasians genotyped for OPRM1 single nucleotide polymorphisms (SNPs) A118G and C17T and COMT SNPs. The OPRM1 A118G genotype was associated with patients' postoperative Numerical Pain scale (NPS) ratings at 15 min in the postanesthesia care unit (PACU) (p = .01) and patients' sedation scores at 15 min in the PACU (p = .02). COMT genotype (rs4818) was associated with opioid consumption in the first 45 min in the PACU (p = .04). NPS ratings at 45 min were also higher in the group of patients with A/A genotype of rs4680 than in patients with the other two genotypes at this SNP (p = .03). Our haplotype trend analysis identified a COMT haplotype "GCGG" significantly associated with NPS at 15 min (p = .0013), amount of opioids consumed in the first 45 min (p = .0024), and heart rate at 45 min in the PACU (p = .017). The results indicate that genetic variations in COMT contribute to the acute postoperative pain and analgesia responses and physiologic responses in this group of otherwise healthy postoperative orthopedic trauma patients.

Genetic basis of pain variability: recent advances.

An estimated 15-50% of the population experiences pain at any given time, at great personal and societal cost. Pain is the most common reason patients seek medical attention, and there is a high degree of individual variability in reporting the incidence and severity of symptoms. Research suggests that pain sensitivity and risk for chronic pain are complex heritable traits of polygenic origin. Animal studies and candidate gene testing in humans have provided some progress in understanding the heritability of pain, but the application of the genome-wide association methodology offers a new tool for further elucidating the genetic contributions to normal pain responding and pain in clinical populations. Although the determination of the genetics of pain is still in its infancy, it is clear that a number of genes play a critical role in determining pain sensitivity or susceptibility to chronic pain. This review presents an update of the most recent findings that associate genetic variation with variability in pain and an overview of the candidate genes with the highest translational potential.

Pain sensitivity and vasopressin analgesia are mediated by a gene-sex-environment interaction.

Quantitative trait locus mapping of chemical/inflammatory pain in the mouse identified the Avpr1a gene, which encodes the vasopressin-1A receptor (V1AR), as being responsible for strain-dependent pain sensitivity to formalin and capsaicin. A genetic association study in humans revealed the influence of a single nucleotide polymorphism (rs10877969) in AVPR1A on capsaicin pain levels, but only in male subjects reporting stress at the time of testing. The analgesic efficacy of the vasopressin analog desmopressin revealed a similar interaction between the drug and acute stress, as desmopressin inhibition of capsaicin pain was only observed in nonstressed subjects. Additional experiments in mice confirmed the male-specific interaction of V1AR and stress, leading to the conclusion that vasopressin activates endogenous analgesia mechanisms unless they have already been activated by stress. These findings represent, to the best of our knowledge, the first explicit demonstration of analgesic efficacy depending on the emotional state of the recipient, and illustrate the heuristic power of a bench-to-bedside-to-bench translational strategy.

Genetic analysis in the Collaborative Cross breeding population.

Genetic reference populations in model organisms are critical resources for systems genetic analysis of disease related phenotypes. The breeding history of these inbred panels may influence detectable allelic and phenotypic diversity. The existing panel of common inbred strains reflects historical selection biases, and existing recombinant inbred panels have low allelic diversity. All such populations may be subject to consequences of inbreeding depression. The Collaborative Cross (CC) is a mouse reference population with high allelic diversity that is being constructed using a randomized breeding design that systematically outcrosses eight founder strains, followed by inbreeding to obtain new recombinant inbred strains. Five of the eight founders are common laboratory strains, and three are wild-derived. Since its inception, the partially inbred CC has been characterized for physiological, morphological, and behavioral traits. The construction of this population provided a unique opportunity to observe phenotypic variation as new allelic combinations arose through intercrossing and inbreeding to create new stable genetic combinations. Processes including inbreeding depression and its impact on allelic and phenotypic diversity were assessed. Phenotypic variation in the CC breeding population exceeds that of existing mouse genetic reference populations due to both high founder genetic diversity and novel epistatic combinations. However, some focal evidence of allele purging was detected including a suggestive QTL for litter size in a location of changing allele frequency. Despite these inescapable pressures, high diversity and precision for genetic mapping remain. These results demonstrate the potential of the CC population once completed and highlight implications for development of related populations.

Central CRH administration changes formalin pain responses in male and female rats.

Corticotropin-releasing hormone (CRH) is suggested to be involved in the regulation of pain. To better evaluate the CRH-mediated behavioral alterations in the formalin inflammatory pain test, we administered CRH or the CRH receptor antagonist α-helical CRH(9-41) (ahCRH) intracerebroventricularly to male and female rats and compared the effects with those of saline control. Nociceptive stimulation was carried out through a subcutaneous injection of dilute formalin (50µL, 10%) in the plantar surface of the hind paw. In both sexes, formalin-induced responses, recorded for 60min, were affected by CRH but not by ahCRH treatment. Paw flexing duration was decreased in both sexes during the formalin interphase period in the CRH-treated group compared to saline control groups; however, licking of the injected paw was markedly increased by the same treatment at other time periods. Treatments induced only a few changes in spontaneous non-pain behaviors, which do not account for the effects on pain response. In conclusion, these data demonstrate the ability of CRH to affect the behavioral responses to an inflammatory nociceptive stimulus, and that the effects can be in opposite directions depending on the behavioral response considered.

Genomic loci and candidate genes underlying inflammatory nociception.

Heritable genetic factors contribute significantly to inflammatory nociception. To determine candidate genes underlying inflammatory nociception, the current study used a mouse model of abdominal inflammatory pain. BXD recombinant inbred (RI) mouse strains were administered the intraperitoneal acetic acid test, and genome-wide quantitative trait locus (QTL) mapping was performed on the mean number of abdominal contraction and extension movements in 3 distinct groups of BXD RI mouse strains in 2 separate experiments. Combined mapping results detected 2 QTLs on chromosomes (Chr) 3 and 10 across experiments and groups of mice; an additional sex-specific QTL was detected on Chr 16. The results replicate previous findings of a significant QTL, Nociq2, on distal Chr 10 for formalin-induced inflammatory nociception and will aid in identification of the underlying candidate genes. Comparisons of sensitivity to intraperitoneal acetic acid in BXD RI mouse strains with microarray mRNA transcript expression profiles in specific brain areas detected covarying expression of candidate genes that are also found in the detected QTL confidence intervals. The results indicate that common and distinct genetic mechanisms underlie heritable sensitivity to diverse inflammatory insults, and provide a discrete set of high-priority candidate genes to investigate further in rodents and human association studies. Novel genomic regions linked to inflammatory nociception were detected, a previously reported locus was confirmed, and high-priority candidate genes for inflammatory nociception and pain were identified.

The nociceptive and anti-nociceptive effects of bee venom injection and therapy: a double-edged sword.

Bee venom injection as a therapy, like many other complementary and alternative medicine approaches, has been used for thousands of years to attempt to alleviate a range of diseases including arthritis. More recently, additional theraupeutic goals have been added to the list of diseases making this a critical time to evaluate the evidence for the beneficial and adverse effects of bee venom injection. Although reports of pain reduction (analgesic and antinociceptive) and anti-inflammatory effects of bee venom injection are accumulating in the literature, it is common knowledge that bee venom stings are painful and produce inflammation. In addition, a significant number of studies have been performed in the past decade highlighting that injection of bee venom and components of bee venom produce significant signs of pain or nociception, inflammation and many effects at multiple levels of immediate, acute and prolonged pain processes. This report reviews the extensive new data regarding the deleterious effects of bee venom injection in people and animals, our current understanding of the responsible underlying mechanisms and critical venom components, and provides a critical evaluation of reports of the beneficial effects of bee venom injection in people and animals and the proposed underlying mechanisms. Although further studies are required to make firm conclusions, therapeutic bee venom injection may be beneficial for some patients, but may also be harmful. This report highlights key patterns of results, critical shortcomings, and essential areas requiring further study.

The genetics of pain and analgesia in laboratory animals.

Pain and analgesia traits are heritable in humans and in mice. To better understand the mechanisms of heritability, animal models that provide greater control than is possible in humans over genotype, previous history, environment, and stimulus parameters are available. This chapter will highlight several common methods to study the genetic mechanisms of heritable sensitivity to pain and pain-related traits in rodents. Methods to demonstrate and estimate the heritability of a trait are discussed, as are genetic correlation analysis and linkage mapping. Practical concerns are highlighted throughout this chapter. Due to limitations on the use of humans for similarly powered experiments, these and other animal models remain an essential component in the study of heritable mechanisms of pain and analgesia.

Alcohol-induced tolerance and physical dependence in mice with ethanol insensitive alpha1 GABA A receptors.

BACKGROUND: Although many people consume alcohol (ethanol), it remains unknown why some become addicted. Elucidating the molecular mechanisms of tolerance and physical dependence (withdrawal) may provide insight into alcohol addiction. While the exact molecular mechanisms of ethanol action are unclear, gamma-aminobutyric acid type A receptors (GABA(A)-Rs) have been extensively implicated in ethanol action. The alpha1 GABA(A)-R subunit is associated with tolerance and physical dependence, but its exact role remains unknown. In this report, we tested the hypothesis that alpha1-GABA(A)-Rs mediate in part these effects of ethanol. METHODS: Ethanol-induced behavioral responses related to tolerance and physical dependence were investigated in knockin (KI) mice that have ethanol-insensitive alpha1 GABA(A)-Rs and wildtype (WT) controls. Acute functional tolerance (AFT) was assessed using the stationary dowel and loss of righting reflex (LORR) assays. Chronic tolerance was assessed on the LORR, fixed speed rotarod, hypothermia, and radiant tail-flick assays following 10 consecutive days of ethanol exposure. Withdrawal-related hyperexcitability was assessed by handling-induced convulsions following 3 cycles of ethanol vapor exposure/withdrawal. Immunoblots were used to assess alpha1 protein levels. RESULTS: Compared with controls, KI mice displayed decreased AFT and chronic tolerance to ethanol-induced motor ataxia, and also displayed heightened ethanol-withdrawal hyperexcitability. No differences between WT and KI mice were seen in other ethanol-induced behavioral measures. Following chronic exposure to ethanol, control mice displayed reductions in alpha1 protein levels, but KIs did not. CONCLUSIONS: We conclude that alpha1-GABA(A)-Rs play a role in tolerance to ethanol-induced motor ataxia and withdrawal-related hyperexcitability. However, other aspects of behavioral tolerance and physical dependence do not rely on alpha1-containing GABA(A)-Rs.

Gene therapy and chronic pain.

Chronic, unremitting pain is perhaps the most common reason that patients seek medical care. In general, conservative techniques, such as medical management, are implemented as first-line therapy. Local anesthesia and lytic procedures, followed by interventional techniques, such as dorsal column stimulation and intrathecal drug delivery systems, are second-line therapies. However, for refractory and severe pain, which is not adequately controlled by other modes of therapy, new emerging options, including molecular or gene therapy, may become more widely utilized as experimental results are translated into clinical options.

Inflammation-susceptible Lewis rats show less sensitivity than resistant Fischer rats in the formalin inflammatory pain test and with repeated thermal testing.

Comparisons between Lewis and Fischer inbred strains of rats are used frequently to study the effect of inherent differences in function of the hypothalamic-pituitary-adrenal axis on pain-relevant traits, including differential susceptibility to chronic inflammatory disease and differential responsiveness to analgesic drugs. Increasing use of genetic models including transgenic knockout mice and inbred strains of rodents has raised our awareness of, and the importance of, thorough characterization (or phenotyping) of the strains of rodents being compared. Furthermore, genetic variability in analgesic sensitivity is correlated with, and may be caused by, genetically determined baseline sensitivity. Thus in this study, baseline inflammatory and thermal nociceptive sensitivities were measured in awake male and female Lewis and Fischer rats to examine whether the results could explain relevant strain differences reported in the literature. The effect of maternal separation was also examined and no effect was found on nociceptive sensitivity, corticosterone responses, or the development of adjuvant-induced arthritis, a model of rheumatoid arthritis. Lewis rats and female rats were more sensitive to thermal nociception in the tail withdrawal test (mean of 3 trials) than Fischer rats and male rats, respectively. Unexpectedly, the more inflammation-susceptible Lewis rats were less sensitive in the formalin inflammatory nociception test, and showed a significant decrease in sensitivity with repeated thermal nociceptive testing, whereas Fischer rats did not. These results affect the interpretation of previously observed results. Further study of the underlying mechanisms and the relevance to differential susceptibility to chronic inflammation is warranted.