Hot off the presses! Mar 01 Alcohol Alcohol

The Mar 01 issue of the Alcohol Alcohol is now up on Pubget (About Alcohol Alcohol): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Special Issue on Alcohol and Brain Damage
  Chick J de Witte P - Alcohol Alcohol 44(2):105 (2009)
  
• Introduction to This Issue: The Seven Ages of Man ... (or Woman)
  Marshall EJ Guerrini I Thomson AD - Alcohol Alcohol 44(2):106-107 (2009)
  
• Foetal Alcohol Spectrum Disorders and Alterations in Brain and Behaviour
  Guerri C Bazinet A Riley EP - Alcohol Alcohol 44(2):108-114 (2009)
  The term Foetal Alcohol Spectrum Disorders (FASD)' refers to the range of disabilities that may result from prenatal alcohol exposure. This article reviews the effects of ethanol on the developing brain and its long-term structural and neurobehavioural consequences. Brain imaging, neurobehavioural and experimental studies demonstrate the devastating consequences of prenatal alcohol exposure on the developing central nervous system (CNS), identifying specific brain regions affected, the range of severity of effects and mechanisms involved. In particular, neuroimaging studies have demonstrated overall and regional volumetric and surface area reductions, abnormalities in the shape of particular brain regions, and reduced and increased densities for white and grey matter, respectively. Neurobehaviourally, FASD consists of a continuum of long-lasting deficits affecting multiple aspects of cognition and behaviour. Experimental studies have also provided evidence of the vuln! erability of the CNS to the teratogenic effects of ethanol and have provided new insight on the influence of risk factors in the type and severity of observed brain abnormalities. Finally, the potential molecular mechanisms that underlie the neuroteratological effects of alcohol are discussed, with particular emphasis on the role of glial cells in long-term neurodevelopmental liabilities.
• Mechanisms of Neurodegeneration and Regeneration in Alcoholism
  Crews FT Nixon K - Alcohol Alcohol 44(2):115-127 (2009)
  Aims: This is a review of preclinical studies covering alcohol-induced brain neuronal death and loss of neurogenesis as well as abstinence-induced brain cell genesis, e.g. brain regeneration. Efforts are made to relate preclinical studies to human studies. Methods: The studies described are preclinical rat experiments using a 4-day binge ethanol treatment known to induce physical dependence to ethanol. Neurodegeneration and cognitive deficits following binge treatment mimic the mild degeneration and cognitive deficits found in humans. Various histological methods are used to follow brain regional degeneration and regeneration. Results: Alcohol-induced degeneration occurs due to neuronal death during alcohol intoxication. Neuronal death is related to increases in oxidative stress in brain that coincide with the induction of proinflammatory cytokines and oxidative enzymes that insult brain. Degeneration is associated with increased NF-{kappa}B proinflammatory transcripti! on and decreased CREB transcription. Corticolimbic brain regions are most sensitive to binge-induced degeneration and induce relearning deficits. Drugs that block oxidative stress and NF-{kappa}B transcription or increase CREB transcription block binge-induced neurodegeneration, inhibition of neurogenesis and proinflammatory enzyme induction. Regeneration of brain occurs during abstinence following binge ethanol treatment. Bursts of proliferating cells occur across multiple brain regions, with many new microglia across brain after months of abstinence and many new neurons in neurogenic hippocampal dentate gyrus. Brain regeneration may be important to sustain abstinence in humans. Conclusions: Alcohol-induced neurodegeneration occurs primarily during intoxication and is related to increased oxidative stress and proinflammatory proteins that are neurotoxic. Abstinence after binge ethanol intoxication results in brain cell genesis that could contribute to the return of brain f! unction and structure found in abstinent humans.
• Biochemical and Neurotransmitter Changes Implicated in Alcohol-Induced Brain Damage in Chronic or 'Binge Drinking' Alcohol Abuse
  Ward RJ Lallemand F de Witte P - Alcohol Alcohol 44(2):128-135 (2009)
  The brain damage, which occurs after either chronic alcoholization or binge drinking regimes, shows distinct biochemical and neurotransmitter differences. An excessive amount of glutamate is released into specific brain regions during binge drinking (in excess of 4- to 5-fold of the normal basal concentration) that is not evident during periods of excessive alcohol consumption in chronic alcohol abusers. Increases in glutamate release are only observed during the initial stages of withdrawal from chronic alcoholism ([~]2- to 3-fold) due to alterations in the sensitivities of the NMDA receptors. Such changes in either density or sensitivity of these receptors are reported to be unaltered by binge drinking. When such excesses of glutamate are released in these two different models of alcohol abuse, a wide range of biochemical changes occur, mediated in part by increased fluxes of calcium ions and/or activation of various G-protein-associated signalling pathways. Cellular! studies of alveolar macrophages isolated from these two animal models of alcohol abuse showed enhanced (binge drinking) or reduced (chronic alcoholization) lipopolysaccharide (LPS)-stimulated NO release. Such studies could suggest that neuroadaptation occurs with the development of tolerance to alcohol's effects in both neurotransmitter function and cellular processes during chronic alcoholization that delay the occurrence of brain damage. In contrast, binge drinking' induces immediate and toxic effects and there is no evidence of an increased preference for alcohol as seen after withdrawal from chronic alcoholization.
• The Neuropathology of Alcohol-Related Brain Damage
  Harper C - Alcohol Alcohol 44(2):136-140 (2009)
  Excessive alcohol use can cause structural and functional abnormalities of the brain and this has significant health, social and economic implications for most countries in the world. Even heavy social drinkers who have no specific neurological or hepatic problems show signs of regional brain damage and cognitive dysfunction. Changes are more severe and other brain regions are damaged in patients who have additional vitamin B1 (thiamine) deficiency (Wernicke-Korsakoff syndrome). Quantitative studies and improvements in neuroimaging have contributed significantly to the documentation of these changes but mechanisms underlying the damage are not understood. A human brain bank targeting alcohol cases has been established in Sydney, Australia, and tissues can be used for structural and molecular studies and to test hypotheses developed from animal models and in vivo studies. The recognition of potentially reversible changes and preventative medical approaches are important! public health issues.
• Update of Cell Damage Mechanisms in Thiamine Deficiency: Focus on Oxidative Stress, Excitotoxicity and Inflammation
  Hazell AS Butterworth RF - Alcohol Alcohol 44(2):141-147 (2009)
  Thiamine deficiency (TD) is a well-established model of Wernicke's encephalopathy. Although the neurologic dysfunction and brain damage resulting from the biochemical consequences of TD is well characterized, the mechanism(s) that lead to the selective histological lesions characteristic of this disorder remain a mystery. Over the course of many years, various structural and functional changes have been identified that could lead to cell death in this disorder. However, despite a concerted effort to explain the consequences of TD in terms of these changes, our understanding of the pathophysiology of this disorder remains unclear. This review will focus on three of these processes, i.e. oxidative stress, glutamate-mediated excitotoxicity and inflammation and their role in selective vulnerability in TD. Since TD inhibits oxidative metabolism, a feature of many neurodegenerative disease states, it represents a model system with which to explore pathological mechanisms inh! erent in such maladies, with the potential to yield new insights into their possible treatment and prevention.
• The Korsakoff Syndrome: Clinical Aspects, Psychology and Treatment
  Kopelman MD Thomson AD Guerrini I Marshall EJ - Alcohol Alcohol 44(2):148-154 (2009)
  Aims: The Korsakoff syndrome is a preventable memory disorder that usually emerges (although not always) in the aftermath of an episode of Wernicke's encephalopathy. The present paper reviews the clinical and scientific literature on this disorder. Methods: A systematic review of the clinical and scientific literature on Wernicke's encephalopathy and the alcoholic Korsakoff syndrome. Results: The Korsakoff syndrome is most commonly associated with chronic alcohol misuse, and some heavy drinkers may have a genetic predisposition to developing the syndrome. The characteristic neuropathology includes neuronal loss, micro-haemorrhages and gliosis in the paraventricular and peri-aqueductal grey matter. Lesions in the mammillary bodies, the mammillo-thalamic tract and the anterior thalamus may be more important to memory dysfunction than lesions in the medial dorsal nucleus of the thalamus. Episodic memory is severely affected in the Korsakoff syndrome, and the learning of n! ew semantic memories is variably affected. Implicit' aspects of memory are preserved. These patients are often first encountered in general hospital settings where they can occupy acute medical beds for lengthy periods. Abstinence is the cornerstone of any rehabilitation programme. Korsakoff patients are capable of new learning, particularly if they live in a calm and well-structured environment and if new information is cued. There are few long-term follow-up studies, but these patients are reported to have a normal life expectancy if they remain abstinent from alcohol. Conclusions: Although we now have substantial knowledge about the nature of this disorder, scientific questions (e.g. regarding the underlying genetics) remain. More particularly, there is a dearth of appropriate long-term care facilities for these patients, given that empirical research has shown that good practice has beneficial effects.
• Neuroimaging of the Wernicke-Korsakoff Syndrome
  Sullivan EV Pfefferbaum A - Alcohol Alcohol 44(2):155-165 (2009)
  Aim: Presented is the neuroradiological signature of acute Wernicke's encephalopathy (WE), derived from different types of magnetic resonance imaging (MRI) sequences. WE results from thiamine depletion, and its most typical antecedent is chronic alcohol dependence. Brain regions observed with in vivo MRI affected in acute WE include the mammillary bodies, periaqueductal and periventricular gray matter, collicular bodies and thalamus. These affected areas are usually edematous and are best visualized and quantified with MRI sequences that highlight such tissue. Following the acute WE phase and resolution of edema and inflammation of affected brain tissue, WE, if not adequately treated with thiamine repletion, can herald Korsakoff's syndrome (KS), with its symptomatic hallmark of global amnesia, that is, the inability to commit newly encountered (episodic) information to memory for later recall or recognition. Methods: Neuropathology of KS detectable with MRI has a diffe! rent neuroradiological signature from the acute stage and can be observed as tissue shrinkage or atrophy of selective brain structures, including the mammillary bodies and thalamus and ventricular expansion, probably indicative of atrophy of surrounding gray matter nuclei. Quantification of these and additional gray matter structures known to underlie global amnesia reveal substantial bilateral volume deficits in the hippocampus, in addition to the mammillary bodies and thalamus, and modest deficits in the medial septum/diagonal band of Broca. The infratentorium is also affected, exhibiting volume deficits in cerebellar hemispheres, anterior superior vermis and pons, contributing to ataxia of gait and stance. Results: Consideration of WKS structural brain changes in the context of the neuropathology of non-WKS alcoholism revealed a graded pattern of volume deficits, from mild in non-WKS alcoholics to moderate or severe in WKS, in the mammillary bodies, hippocampus, thalamus! , cerebellum and pons. The development and resolution of brain! structures affected in acute, chronic and treated WE was verified in longitudinal MRI study of rats that modeled of the interaction of extensive alcohol consumption and thiamine depletion and repletion. Conclusions: Thus, neuroradiological examination with MRI is valuable in the diagnosis of acute WE and enables in vivo tracking of the progression of the brain pathology of WE from the acute pathological phase to resolution with thiamine treatment or to progression to KS without treatment. Further, in vivo MRI facilitates translational studies to model antecedent conditions contributing to the development, sequelae and treatment of WE.
• Molecular Genetics of Alcohol-Related Brain Damage
  Guerrini I Thomson AD Gurling HM - Alcohol Alcohol 44(2):166-170 (2009)
  Aims: In the scientific literature it has been repeatedly hypothesized that there is a heritable susceptibility to thiamine deficiency comparable to other hereditary metabolic disorders. The aim of this paper is to review the most recent knowledge on the genetic susceptibility to the development of alcohol-related Wernicke-Korsakoff syndrome (WKS). Methods: A literature review was carried out looking at the molecular genetics studies performed in alcohol-dependent patients affected by WKS. Results: A genetic component in the pathogenesis of WKS has been postulated since the late seventies. Since then, very few genetic studies have been carried out on candidate genes such as thiamine-dependent enzymes, alcohol-metabolizing enzymes and GABA receptors. The findings are controversial and not conclusive. Several authors reported the important role of the thiamine transporters in the pathogenesis of the thiamine deficiency disorders. Our findings on SLC19A2 and SLC19A3 sugge! st a potential role of these two genes in the pathophysiology of alcohol-related thiamine deficiency but further studies need to be carried out. Conclusions: The WKS may be a very complex, multifactorial disorder where the interaction of multiple genes and environment plays an important role in the pathogenesis. However, it is still plausible that megaphenic gene effects are responsible for WKS susceptibility and the thiamine transport genes are good candidates for having such a role. Further genetic studies are definitely needed to investigate the association with candidate genes or linkage with hot spot areas.
• Proteomics Approach in the Study of the Pathophysiology of Alcohol-Related Brain Damage
  Matsumoto I - Alcohol Alcohol 44(2):171-176 (2009)
  Aims: Chronic, excessive drinking of alcohol can induce brain damage in the regions important for neurocognitive function. Some of the damage are permanent while some are appearantly reversible. It is our aim to understand the molecular mechanisms underlying alcohol-induced and/or related brain damage, particularly of that observed in medically uncomplicated' (without heptatic cirrhosis or Wernicke-Korsakoff Syndrome [WKS]) alcoholics. Methods: A high-throughput proteomics technology has been applied to several alcohol-sensitive' brain regions from uncomplicated and hepatic cirrhosis-complicated alcoholics to understand the mechanisms of alcohol-related brain damage at the level of protein expression. Results: It was clearly demonstrated that each brain region reacts in significantly different manner to chronic alcohol ingestion. Appearant abnormalities in vitamin B1 (thiamine)-related biochemical pathways were observed in several brain regions, such as the dorsolate! ral prefrontal cortex, genu (a frontal part of the corpus callosum) and cerebellar vermis in uncomplicated alcoholics, suggesting that the reduction of this important nutritional component might be associated with brain damage even without the signs of WKS. In addition, in the two different subregions of the corpus callosum (genu and splenium [a posterior part of the corpus callosum]) and the cerebellar vermis, significant differences in protein expression profiles between uncomplicated and complicated alcoholics with hepatic cirrhosis were identified, suggesting that hepatic factors such as ammonia have significant additive influences on brain protein expression, which might lead to the structural changes and/or damage in these brain regions. Furthermore, in the hippocampus, significant change of the level of glutamine synthetase expression was observed, suggesting once again the importance of ammonia as a cause of brain damage in this region. Conclusions: Although our dat! a did not show any evidence of "direct" alcohol effects to ind! uce the alteration of protein expression in association with brain damage, high-throughput neuroproteomics approaches are proven to have a potential to dissect the mechanisms of complex brain disorders.
• Biomarkers in Alcohol Misuse: Their Role in the Prevention and Detection of Thiamine Deficiency
  Mancinelli R Ceccanti M - Alcohol Alcohol 44(2):177-182 (2009)
  In Western countries alcohol misuse is the most frequent cause of thiamine (vitamin B1) deficiency (TD) and consequent neuro-impairment. Studies have demonstrated that between 30 and 80% of alcoholics are thiamine deficient, and this puts them at risk of developing the Wernicke-Korsakoff (WK) syndrome. The relative roles of alcohol and TD in causing brain damage remain controversial and it is important to try to determine the role played by each factor. Animal studies support an additive effect of alcohol exposure and TD, and indicate the potential for interaction between alcohol and TD in human alcohol-related brain damage. Early diagnosis of alcohol-related TD is therefore an important aspect of effective intervention and treatment. Alcohol biomarkers provide a direct and indirect way of estimating the amount of alcohol being consumed, the duration of ingestion and the harmful effects that long-term alcohol use has on body functions. Appropriate use of these markers ! is very helpful when considering a diagnosis of alcohol-related TD.
• Alcohol Withdrawal and Prolonged Hospital Stay in a Patient with Neuroimaging Abnormalities: A Case Report
  Gupta M - Alcohol Alcohol 44(2):183-184 (2009)
  A hospital stay of 30 days was required in a 47-year-old woman with alcohol withdrawal. Magnetic resonance imaging (MRI) findings revealed a focal brain stem lesion and multiple focal supracortical abnormalities. Could asymptomatic neuroimaging abnormalities predict risk of complicated alcohol withdrawal? Future clinical observations and longitudinal studies may wish to address this potential risk factor.
• In vitro Neurogenesis from Neural Progenitor Cells Isolated from the Hippocampus Region of the Brain of Adult Rats Exposed to Ethanol during Early Development through Their Alcohol-Drinking Mothers
  Singh AK Gupta S Jiang Y Younus M Ramzan M - Alcohol Alcohol 44(2):185-198 (2009)
  Aims: This study was aimed to determine whether ethanol exposure during early development altered neurogenesis in the brain of adult rats. Methods: Pregnant rats were given either ethanol-mixed or mannose-mixed (for control) rodent liquid diet ad libitum. Ethanol drinking continued during pregnancy and nursing. After weaning, the pups (ACo: pups from control mothers, AEo: pups from ethanol exposed mothers) received normal diet and water ad libitum for 11 weeks. Then the rats were anesthetized, their brains were collected and the hippocampal samples were processed for isolation of neural progenitor cells (NPCs). ACo NPCs and AEo NPCs were sequentially grown in media containing different growth factors that induced proliferation and differentiation. Results and Conclusions: Neuronal maturation was significantly delayed in ethanol-exposed rats. ACo NPCs, up to day 7 of culture, exhibited high {beta}-catenin-probe binding, an increase in Ca2+ when exposed to {gamma}-amino ! butyric acid (GABA) and lack of response to glutamate (Glu) exposure. {beta}-Catenin-probe binding and the stimulatory effects of GABA declined thereafter. ACo NPCs, at culture day 29, exhibited high {beta}-catenin-probe binding, lack of response to GABA and elevated Glu-induced increase in Ca2+i. Cultures of AEo NPCs showed an amplified stimulatory effects of GABA, attenuated stimulatory effects of Glu and attenuated the delayed (culture day 29) increase in the expression of Wnt proteins and {beta}-catenin-probe binding. This suggests a significant alteration in neurogenesis and synapse formation in adult rats exposed to ethanol at early development through their alcohol-drinking mothers.
• Biomarkers of Liver Status in Heavy Drinkers, Moderate Drinkers and Abstainers
  Alatalo P Koivisto H Puukka K Hietala J Anttila P Bloigu R Niemelä O - Alcohol Alcohol 44(2):199-203 (2009)
  Aims: Although a wide variety of biomarkers reflecting liver status are known to be influenced by excessive ethanol consumption, the dose-response relationships between ethanol intake and marker changes have remained less understood. Methods: Serum gamma-glutamyltransferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT) activities, and ferritin and albumin protein concentrations were compared in a large population of heavy drinkers (105 men, 28 women), moderate drinkers (781 men, 723 women) and abstainers (252 men, 433 women), who were devoid of apparent liver disease. Results: In heavy drinkers, serum GGT, AST, ALT, ferritin and albumin were all significantly higher than in moderate drinkers or abstainers (P < 0.001 for all comparisons). The highest incidences of elevated values were found for GGT (62%) followed by AST (53%), ALT (39%), ferritin (34%) and albumin (20%). Serum GGT (P < 0.001), ALT (P < 0.01) and ferritin (P < 0.05) in moderate ! drinkers were also higher than the levels observed in abstainers. When the study population was further divided into subgroups according to gender, significant differences between moderate drinkers and abstainers in GGT and ALT were noted in men whereas not in women. Conclusions: The data demonstrate that biomarkers of alcohol abuse and liver function may respond to even rather low levels of ethanol intake in a gender-dependent manner, which should be implicated in studies on the early-phase interactions of ethanol and the liver and in the definition of normal ranges for such biomarkers.
• Impact of Body Weight on the Relationship between Alcohol Intake and Blood Pressure
  Wakabayashi I - Alcohol Alcohol 44(2):204-210 (2009)
  Aims: The reduction of habitual alcohol drinking is recommended for the prevention of hypertension. Daily or weekly alcohol consumption, which is used for evaluation of the effects of alcohol drinking on blood pressure, is usually not corrected by body weight. In this study, the influence of body weight on the relationship between alcohol intake and blood pressure was investigated.Methods: The subjects (27,005 healthy men at ages of 35-54 years) were divided into four groups by average daily ethanol intake [non-, light (<15 g per day), moderate ([≥]15 and <30 g per day) and heavy ([≥]30 g per day) drinkers]. The subjects were also divided into four quartile groups by body weight.Results: Alcohol intake and the percentage of drinkers were not different in the four quartile groups of body weight. In the first and second quartiles of body weight, systolic and diastolic blood pressures were significantly higher in moderate and heavy drinkers than in non-drinkers, whi! le systolic and diastolic blood pressures in the fourth quartile of body weight were significantly higher in heavy drinkers than in non-drinkers but were not significantly different in moderate drinkers and non-drinkers. The differences in systolic or diastolic blood pressure between non-drinkers and moderate drinkers and between non-drinkers and heavy drinkers became greater as body weight decreased. These results were not altered when age and smoking history were adjusted.Conclusions: The results suggest that body weight modifies the relationship between alcohol consumption and blood pressure and thus should be taken into account when effects of alcohol on blood pressure are considered.
• Is Cortisol Involved in the Alcohol-Related Fat Mass Impairment? A Longitudinal Clinical Study
  Leggio L Malandrino N Ferrulli A Cardone S Miceli A Gasbarrini G Capristo E Addolorato G - Alcohol Alcohol 44(2):211-215 (2009)
  Aims: Subjects with chronic alcohol abuse can present several metabolic and nutritional alterations. The hypothalamic-pituitary-adrenal (HPA) axis may play a role in these nutritional and metabolic disorders. The goal of this study was to investigate if there is any relationship between HP-hormones and metabolic and nutritional parameters in alcoholic subjects. Methods: Sixteen alcoholics were considered before and after 3 months of total alcohol abstinence. HP-related hormones were determined. Nutritional and metabolic parameters were assessed by dual-energy X-ray absorptiometry (DXA) and indirect calorimetry. Results: At baseline, a significant negative correlation was found between fat mass (FM) and cortisol (r = -0.54, P = 0.03). During abstinence, a significant increase of both body mass index (BMI) (P < 0.0001) and FM (P < 0.0001) was found at 12 weeks compared to baseline. A significant decrease of both plasma cortisol (P = 0.044) and aldosterone (P = 0.023) was! found at 12 weeks compared to baseline. At 12 weeks, the significant correlation between cortisol and FM disappeared. Conclusions: A higher HPA-axis activation--reflected by higher cortisol levels--was associated with a lower FM in alcoholics. Conversely, during total abstinence a reduced HPA-axis activity can play a role in the parallel nutritional recovery. The present results suggest a role of the HPA axis throughout cortisol both in the etiology of the alcohol-related nutritional alterations and in their recovery after a period of total alcohol abstinence.
• Reported Beverage Consumed and Alcohol-Related Diseases among Male Hospital Inpatients with Problem Drinking
  Coder B Freyer-Adam J Lau K Riedel J Rumpf HJ Meyer C John U Hapke U - Alcohol Alcohol 44(2):216-221 (2009)
  Aims: The aim of this study was to examine if problem drinkers have varying risks of having alcohol-related diseases according to their reported beverage consumed. Methods: In a cross-sectional study all consecutive inpatients aged 18- 64 years from four general hospitals of one catchment area were systematically screened for alcohol use. A total of 1011 men with problem drinking were used for this study. Routine treatment diagnoses for all participants were provided by hospital physicians and were classified into three categories according to their alcohol-attributable fractions (AAF; AAF = 0; AAF < 1; AAF = 1). Results: According to their reported beverage consumed, 53.0% of the participants were identified as exclusively beer drinkers, 14.1% exclusively spirits drinkers, 26.0% mixed beer and spirits drinkers and 6.9% individuals drinking wine exclusively or in combination with one or two other beverages (mixed wine drinkers). Compared to spirits drinkers and control! ling for possible confounders (i.e. alcohol-associated characteristics, demographic variables), multinomial regressions revealed that beer drinkers, mixed beer and spirits drinkers, and mixed wine drinkers had lower odds of having diseases with AAF = 1 than spirits drinkers (e.g. for AAF = 1: beer versus spirits drinkers: OR = 0.42, CI: 0.25-0.72). Beer drinkers and mixed wine drinkers also had lower odds of having diseases with AAF < 1 than spirits drinkers (e.g. mixed wine versus spirits drinkers: OR = 0.36, CI: 0.18-0.72). Conclusions: These data suggest an association between the reported beverage consumed and alcohol-related diseases. Among hospitalized problem drinkers, spirits drinkers had the greatest risk of having diseases with AAF < 1 and with AAF = 1.

Hot off the presses! Jan 01

The Jan 01 issue of the is now up on Pubget (About ): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• From the editors
  - Nature Reviews Neuroscience 11(1):1 (2010)
  The establishment of neural circuits during development and their constant fine-tuning during maturation and adulthood require the nervous system to be highly adaptive.Correlated network activity is thought to be required for the development of neural circuits.
• Addiction: Cannabis against heroin?
  - Nature Reviews Neuroscience 11(1):3 (2010)
  Relapse after addictive-drug withdrawal is a big societal problem and is thought to be induced by environmental cues. The identification of treatments that attenuate cue-induced relapse is one aim of addiction research.
• Neurodegenerative disease: Synergistic destruction
  - Nature Reviews Neuroscience 11(1):4 (2010)
  The pathology of Alzheimer's disease (AD) is characterized by amyloid plaques (aggregates of amyloid-β (Aβ)) and fibrillar tangles (aggregates of tau). Mitochondrial dysfunction has also been recognized as being part of the AD pathology, but the mechanisms underlying this dysfunction are poorly understood.
• Neuronal migration: Cadherin keeps order
  - Nature Reviews Neuroscience 11(1):4 (2010)
  Cadherins are adhesion molecules with important roles in CNS development. Köster and colleagues now report in PLoS Biology that N-cadherin (also known as cadherin 2) is required for maintaining cell–cell contacts and cell polarity in granule cells (GCs) during directional migration.
• Evolution: Talking about FOXP2
  - Nature Reviews Neuroscience 11(1):5 (2010)
  The use of language is a uniquely human characteristic; however, the molecular changes that led to the evolution of human speech are largely unknown. Konopka et al.FOXP2), a transcription factor that is important for speech, alter the neuronal expression of a panel of genes, providing insight into the contribution of this protein to the development of speech.
• Circadian rhythms: Cycling vesicles for a cycling SCN
  - Nature Reviews Neuroscience 11(1):5 (2010)
  The suprachiasmatic nucleus (SCN) in the hypothalamus controls the circadian rhythmicity of many physiological processes through clock genes that are expressed in a cyclical fashion. The products of these genes in turn regulate the daily expression of many other genes.
• Synaptic plasticity: Plasticity moves upstream
  - Nature Reviews Neuroscience 11(1):6 (2010)
  Neuronal activity can increase or decrease the strength of synapses between two neurons through long-term potentiation (LTP) and long-term depression (LTD), respectively. Now, Poo and colleagues show that, in vivo, LTP and LTD can spread to the upstream synapse.
• Neurological disorders: Inhibition: too much of a good thing?
  - Nature Reviews Neuroscience 11(1):6 (2010)
  Absence seizures, characterized by a spike and wave discharge (SWD) pattern in thalamocortical networks, occur in many types of epilepsy. The cellular mechanisms underlying these seizures are unclear; however, a new paper by Cope et al.
• In brief: Synapse formation, Learning and memory, Neurological disorders, Development
  - Nature Reviews Neuroscience 11(1):6 (2010)
  Thrombospondin 1 accelerates synaptogenesis in hippocampal neurons through neuroligin 1 Xu, J.et al. Nature Neurosci.15 Nov 2009 (doi:10.1038/nn.2459)
• In brief: Chemosensation, Gap junctions, Fear, Visual system
  - Nature Reviews Neuroscience 11(1):7 (2010)
  Structural requirements for the activation of vomeronasal sensory neurons by MHC peptides Leinders-Zufall, T.et al. Nature Neurosci. 12, 1551–1558 (2009)
• Sex differences in molecular neuroscience: from fruit flies to humans
  - Nature Reviews Neuroscience 11(1):9 (2010)
  A plethora of discoveries relating to sex influences on brain function is rapidly moving this field into the spotlight for most areas of neuroscience. The domain of molecular or genetic neuroscience is no exception. The goal of this article is to highlight key developments concerning sex-based dimorphisms in molecular neuroscience, describe control mechanisms regulating these differences, address the implications of these dimorphisms for normal and abnormal brain function and discuss what these advances mean for future work in the field. The overriding conclusion is that, as for neuroscience in general, molecular neuroscience has to take into account potential sex influences that might modify signalling pathways.
• Mechanisms underlying spontaneous patterned activity in developing neural circuits
  Blankenship AG Feller MB - Nature Reviews Neuroscience 11(1):18 (2010)
  Patterned, spontaneous activity occurs in many developing neural circuits, including the retina, the cochlea, the spinal cord, the cerebellum and the hippocampus, where it provides signals that are important for the development of neurons and their connections. Despite there being differences in adult architecture and output across these various circuits, the patterns of spontaneous network activity and the mechanisms that generate it are remarkably similar. The mechanisms can include a depolarizing action of GABA (γ-aminobutyric acid), transient synaptic connections, extrasynaptic transmission, gap junction coupling and the presence of pacemaker-like neurons. Interestingly, spontaneous activity is robust; if one element of a circuit is disrupted another will generate similar activity. This research suggests that developing neural circuits exhibit transient and tunable features that maintain a source of correlated activity during crucial stages of development.
• The cerebellar microcircuit as an adaptive filter: experimental and computational evidence
  Dean P Porrill J Ekerot CF Jörntell H - Nature Reviews Neuroscience 11(1):30 (2010)
  Initial investigations of the cerebellar microcircuit inspired the Marr–Albus theoretical framework of cerebellar function. We review recent developments in the experimental understanding of cerebellar microcircuit characteristics and in the computational analysis of Marr–Albus models. We conclude that many Marr–Albus models are in effect adaptive filters, and that evidence for symmetrical long-term potentiation and long-term depression, interneuron plasticity, silent parallel fibre synapses and recurrent mossy fibre connectivity is strikingly congruent with predictions from adaptive-filter models of cerebellar function. This congruence suggests that insights from adaptive-filter theory might help to address outstanding issues of cerebellar function, including both microcircuit processing and extra-cerebellar connectivity.
• Neural reorganization following sensory loss: the opportunity of change
  Merabet LB Pascual-Leone A - Nature Reviews Neuroscience 11(1):44 (2010)
  There is growing evidence that sensory deprivation is associated with crossmodal neuroplastic changes in the brain. After visual or auditory deprivation, brain areas that are normally associated with the lost sense are recruited by spared sensory modalities. These changes underlie adaptive and compensatory behaviours in blind and deaf individuals. Although there are differences between these populations owing to the nature of the deprived sensory modality, there seem to be common principles regarding how the brain copes with sensory loss and the factors that influence neuroplastic changes. Here, we discuss crossmodal neuroplasticity with regards to behavioural adaptation after sensory deprivation and highlight the possibility of maladaptive consequences within the context of rehabilitation.
• Advances in visual perceptual learning and plasticity
  Sasaki Y Nanez JE Watanabe T - Nature Reviews Neuroscience 11(1):53 (2010)
  Visual perceptual learning (VPL) is defined as a long-term improvement in performance on a visual task. In recent years, the idea that conscious effort is necessary for VPL to occur has been challenged by research suggesting the involvement of more implicit processing mechanisms, such as reinforcement-driven processing and consolidation. In addition, we have learnt much about the neural substrates of VPL and it has become evident that changes in visual areas and regions beyond the visual cortex can take place during VPL.
• Neurotalk: improving the communication of neuroscience research
  Illes J Moser MA McCormick JB Racine E Blakeslee S Caplan A Hayden EC Ingram J Lohwater T McKnight P Nicholson C Phillips A Sauvé KD Snell E Weiss S - Nature Reviews Neuroscience 11(1):61 (2010)
  There is increasing pressure for neuroscientists to communicate their research and the societal implications of their findings to the public. Communicating science is challenging, and the transformation of communication by digital and interactive media increases the complexity of the challenge. To facilitate dialogue with the public in this new media landscape, we suggest three courses of action for the neuroscience community: a cultural shift that explicitly recognizes and rewards public outreach, the identification and development of neuroscience communication experts, and ongoing empirical research on the public communication of neuroscience.

Hot off the presses! Apr 01 Brain Res Rev

The Apr 01 issue of the Brain Res Rev is now up on Pubget (About Brain Res Rev): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Spring Pain Research Conference 2008
  - Brain Res Rev 60(1):1 (2009)
  
• Roles of transient receptor potential channels in pain
  - Brain Res Rev 60(1):2-23 (2009)
  Pain perception begins with the activation of primary sensory nociceptors. Over the past decade, flourishing research has revealed that members of the Transient Receptor Potential (TRP) ion channel family are fundamental molecules that detect noxious stimuli and transduce a diverse range of physical and chemical energy into action potentials in somatosensory nociceptors. Here we highlight the roles of TRP vanilloid 1 (TRPV1), TRP melastatin 8 (TRPM8) and TRP ankyrin 1 (TRPA1) in the activation of nociceptors by heat and cold environmental stimuli, mechanical force, and by chemicals including exogenous plant and environmental compounds as well as endogenous inflammatory molecules. The contribution of these channels to pain and somatosensation is discussed at levels ranging from whole animal behavior to molecular modulation by intracellular signaling proteins. An emerging theme is that TRP channels are not simple ion channel transducers of one or two stimuli, but instead! serve multidimensional roles in signaling sensory stimuli that are exceptionally diverse in modality and in their environmental milieu.
• Nucleotide signaling and cutaneous mechanisms of pain transduction
  - Brain Res Rev 60(1):24-35 (2009)
  Sensory neurons that innervate the skin provide critical information about physical contact between the organism and the environment, including information about potentially-damaging stimuli that give rise to the sensation of pain. These afferents also contribute to the maintenance of tissue homeostasis, inflammation and wound healing, while sensitization of sensory afferents after injury results in painful hypersensitivity and protective behavior. In contrast to the traditional view of primary afferent terminals as the sole site of sensory transduction, recent reports have lead to the intriguing idea that cells of the skin play an active role in the transduction of sensory stimuli. The search for molecules that transduce different types of sensory stimuli (mechanical, heat, chemical) at the axon terminal has yielded a wide range of potential effectors, many of which are expressed by keratinocytes as well as neurons. Emerging evidence underscores the importance of nucl! eotide signaling through P2X ionotropic and P2Y metabotropic receptors in pain processing, and implicates nucleotide signaling as a critical form of communication between cells of the skin, immune cells and sensory neurons. It is of great interest to determine whether pathological changes in these mechanisms contribute to chronic pain in human disease states such as complex regional pain syndrome (CRPS). This review discusses recent advances in our understanding of communication mechanisms between cells of the skin and sensory axons in the transduction of sensory input leading to pain.
• Nociceptive sensitization by endothelin-1
  - Brain Res Rev 60(1):36-42 (2009)
  The endogenous peptide endothelin-1 (ET-1), originally identified as a potent vasoconstrictor, plays a role in a number of painful conditions. In this review article we discuss the mechanisms that are essential for local sensitization by subcutaneously administered ET-1, and report evidence of ET-1's ability to sensitize distant regions of the body, through the central nervous system and, likely, coupling through the spinal cord. In addition, we will review the latest information on the role of ET-1 in cancerous and non-cancerous conditions. Cancer pain has indeed been shown to be attenuated by antagonists of endothelin receptors, and ET-1 is known to be secreted by cancer cells of many different histologic types. Furthermore, a growing body of evidence links increased expression and secretion of ET-1 to the occurrence of non-cancer related pain syndromes, such as inflammatory and neuropathic pain syndromes.
• Metabotropic receptors for glutamate and GABA in pain
  - Brain Res Rev 60(1):43-56 (2009)
  Glutamate and γ-amino butyric acid (GABA) are respectively two major excitatory and inhibitory neurotransmitters of the adult mammalian central nervous system. These neurotransmitters exert their action through two types of receptors: ionotropic and metabotropic receptors. While ionotropic receptors are ligand gated ion channels involved in fast synaptic transmission, metabotropic receptors belong to the superfamily of G-protein coupled receptors (GPCRs) and are responsible for the neuromodulatory effect of glutamate and GABA. Metabotropic glutamate receptors (mGluRs) and metabotropic GABA receptors (GABA-B) are present at different levels of the pain neuraxis where they regulate nociceptive transmission and pain. The present review will focus on the role of these receptors in the modulation of pain perception.
• Role of interleukin-1β during pain and inflammation
  - Brain Res Rev 60(1):57-64 (2009)
  The cytokine cascade in pain and inflammatory processes is a tremendously complex system, involving glial, immune, and neuronal cell interactions. IL-1β is a pro-inflammatory cytokine that has been implicated in pain, inflammation and autoimmune conditions. This review will focus on studies that shed light on the critical role of IL-1β in various pain states, including the role of the intracellular complex, the inflammasome, which regulates IL-1β production. Evidence will be presented demonstrating the importance of IL-1β in both the induction of pain and in the maintenance of pain in chronic states, such as after nerve injury. Additionally, the involvement of IL-1β as a key mediator in the interaction between glia and neurons in pain states will be discussed. Taken together, the evidence presented in the current review showing the importance of IL-1β in animal and human pain states, suggests that blockade of IL-1β be considered as a therapeutic opportunity.
• Voltage-gated sodium channels in pain states: Role in pathophysiology and targets for treatment
  - Brain Res Rev 60(1):65-83 (2009)
  Pain is a major unmet medical need which has been causally linked to changes in sodium channel expression, modulation, or mutations that alter channel gating properties or current density in nociceptor neurons. Voltage-gated sodium channels activate (open) then rapidly inactivate in response to a depolarization of the plasma membrane of excitable cells allowing the transient flow of sodium ions thus generating an inward current which underlies the generation and conduction of action potentials (AP) in these cells. Activation and inactivation, as well as other gating properties, of sodium channel isoforms have different kinetics and voltage-dependent properties, so that the ensemble of channels that are present determine the electrogenic properties of specific neurons. Biophysical and pharmacological studies have identified the peripheral-specific sodium channels Nav1.7, Nav1.8 and Nav1.9 as particularly important in the pathophysiology of different pain syndromes, and ! isoform-specific blockers of these channels or targeting their modulators hold the promise of a future effective therapy for treatment of pain.
• Role of voltage-gated calcium channels in ascending pain pathways
  - Brain Res Rev 60(1):84-89 (2009)
  Voltage gated calcium channels (VGCCs) are well established mediators of pain signals in primary afferent neurons. N-type calcium channels are localized to synaptic nerve terminals in laminae 1 and 2 of the dorsal horn where their opening results in the release of neurotransmitters such as glutamate and substance P. The contribution of N-type channels to the processing of pain signals is regulated by alternate splicing of the N-type channel gene, with unique N-type channel splice variants being expressed in small nociceptive neurons. In contrast, T-type VGCCs of the Cav3.2 subtype are likely localized to nerve endings where they regulate cellular excitability. Consequently, inhibition of N-type and Cav3.2 T-type VGCCs has the propensity to mediate analgesia. T-type channel activity is regulated by redox modulation, and can be inhibited by a novel class of small organic blockers. N-type VGCC activity can be potently inhibited by highly selective peptide toxins that are ! delivered intrathecally, and the search for small organic blockers with clinical efficacy is ongoing. Here, we provide a brief overview of recent advances in this area, as presented at the Spring Pain Research conference (Grand Cayman, 2008).
• Peripheral mechanisms of pain and analgesia
  - Brain Res Rev 60(1):90-113 (2009)
  This review summarizes recent findings on peripheral mechanisms underlying the generation and inhibition of pain. The focus is on events occurring in peripheral injured tissues that lead to the sensitization and excitation of primary afferent neurons, and on the modulation of such mechanisms. Primary afferent neurons are of particular interest from a therapeutic perspective because they are the initial generator of noxious impulses traveling towards relay stations in the spinal cord and the brain. Thus, if one finds ways to inhibit the sensitization and/or excitation of peripheral sensory neurons, subsequent central events such as wind-up, sensitization and plasticity may be prevented. Most importantly, if agents are found that selectively modulate primary afferent function and do not cross the blood–brain-barrier, centrally mediated untoward side effects of conventional analgesics (e.g. opioids, anticonvulsants) may be avoided. This article begins with the periphera! l actions of opioids, turns to a discussion of the effects of adrenergic co-adjuvants, and then moves on to a discussion of pro-inflammatory mechanisms focusing on TRP channels and nerve growth factor, their signaling pathways and arising therapeutic perspectives.
• Rapid pain modulation with nuclear receptor ligands
  - Brain Res Rev 60(1):114-124 (2009)
  We discuss and present new data regarding the physiological and molecular mechanisms of nuclear receptor activation in pain control, with a particular emphasis on non-genomic effects of ligands at peroxisome proliferator-activated receptor (PPAR), GPR30, and classical estrogen receptors. PPARα agonists rapidly reduce both acute and chronic pain in a number of pain assays. These effects precede transcriptional anti-inflammatory actions, and are mediated in part by IKca and BKca channels on DRG neurons. In contrast to the peripheral site of action of PPARα ligands, the dorsal horn supports the expression of PPARγ. Intrathecal administration of PPARγ ligands rapidly (≤ 5 min) attenuated mechanical and thermal hypersensitivity associated with nerve injury in a dose-dependent manner that could be blocked with PPARγ antagonists. By contrast, a PPARγ antagonist itself rapidly increased the mechanical allodynia associated with nerve injury. These data suggest that liga! nd-dependent, non-genomic activation of spinal PPARγ decreases behavioral signs of inflammatory and neuropathic pain. We also report that the GPR30 is expressed on cultured sensory neurons, that activation of the receptor elicits signaling to increase calcium accumulation. This signaling may contribute to increased neuronal sensitivity as treatment with the GPR30 agonist induces hyperalgesia. Finally, application of the membrane-impermeable 17β-E2-BSA rapidly (within 15 min) enhanced BK-stimulated inositol phosphate (IP) accumulation and PGE2-mediated cAMP accumulation in trigeminal ganglion cultures. We conclude that nuclear receptor ligands may operate through rapid, non-genomic mechanisms to modulate inflammatory and neuropathic pain.
• Chemokines and pain mechanisms
  - Brain Res Rev 60(1):125-134 (2009)
  The development of new therapeutic approaches to the treatment of painful neuropathies requires a better understanding of the mechanisms that underlie the development of these chronic pain syndromes. It is now well established that astrocytic and microglial cells modulate the neuronal mechanisms of chronic pain in spinal cord and possibly in the brain. In animal models of neuropathic pain following peripheral nerve injury, several changes occur at the level of the first pain synapse between the central terminals of sensory neurons and second order neurons. These neuronal mechanisms can be modulated by pro-nociceptive mediators released by non neuronal cells such as microglia and astrocytes which become activated in the spinal cord following PNS injury. However, the signals that mediate the spread of nociceptive signaling from neurons to glial cells in the dorsal horn remain to be established. Herein we provide evidence for two emerging signaling pathways between injure! d sensory neurons and spinal microglia: chemotactic cytokine ligand 2 (CCL2)/CCR2 and cathepsin S/CX3CL1 (fractalkine)/CX3CR1. We discuss the plasticity of these two chemokine systems at the level of the dorsal root ganglia and spinal cord demonstrating that modulation of chemokines using selective antagonists decrease nociceptive behavior in rodent chronic pain models. Since up-regulation of chemokines and their receptors may be a mechanism that directly and/or indirectly contributes to the development and maintenance of chronic pain, these molecular molecules may represent novel targets for therapeutic intervention in sustained pain states.
• MAP kinase and pain
  - Brain Res Rev 60(1):135-148 (2009)
  Mitogen-activated protein kinases (MAPKs) are important for intracellular signal transduction and play critical roles in regulating neural plasticity and inflammatory responses. The MAPK family consists of three major members: extracellular signal-regulated kinases (ERK), p38, and c-Jun N-terminal kinase (JNK), which represent three separate signaling pathways. Accumulating evidence shows that all three MAPK pathways contribute to pain sensitization after tissue and nerve injury via distinct molecular and cellular mechanisms. Activation (phosphorylation) of MAPKs under different persistent pain conditions results in the induction and maintenance of pain hypersensitivity via non-transcriptional and transcriptional regulation. In particular, ERK activation in spinal cord dorsal horn neurons by nociceptive activity, via multiple neurotransmitter receptors, and using different second messenger pathways plays a critical role in central sensitization by regulating the activi! ty of glutamate receptors and potassium channels and inducing gene transcription. ERK activation in amygdala neurons is also required for inflammatory pain sensitization. After nerve injury, ERK, p38, and JNK are differentially activated in spinal glial cells (microglia vs astrocytes), leading to the synthesis of proinflammatory/pronociceptive mediators, thereby enhancing and prolonging pain. Inhibition of all three MAPK pathways has been shown to attenuate inflammatory and neuropathic pain in different animal models. Development of specific inhibitors for MAPK pathways to target neurons and glial cells may lead to new therapies for pain management. Although it is well documented that MAPK pathways can increase pain sensitivity via peripheral mechanisms, this review will focus on central mechanisms of MAPKs, especially ERK.
• Chloride regulation in the pain pathway
  - Brain Res Rev 60(1):149-170 (2009)
  Melzack and Wall's Gate Control Theory of Pain laid the theoretical groundwork for a role of spinal inhibition in endogenous pain control. While the Gate Control Theory was based on the notion that spinal inhibition is dynamically regulated, mechanisms underlying the regulation of inhibition have turned out to be far more complex than Melzack and Wall could have ever imagined. Recent evidence indicates that an exquisitely sensitive form of regulation involves changes in anion equilibrium potential (Eanion), which subsequently impacts fast synaptic inhibition mediated by GABAA, and to a lesser extent, glycine receptor activation, the prototypic ligand gated anion channels. The cation-chloride co-transporters (in particular NKCC1 and KCC2) have emerged as proteins that play a critical role in the dynamic regulation of Eanion which in turn appears to play a critical role in hyperalgesia and allodynia following peripheral inflammation or nerve injury. This review summarize! s the current state of knowledge in this area with particular attention to how such findings relate to endogenous mechanisms of hyperalgesia and allodynia and potential applications for therapeutics based on modulation of intracellular Cl− gradients or pharmacological interventions targeting GABAA receptors.
• Development, plasticity and modulation of visceral afferents
  - Brain Res Rev 60(1):171-186 (2009)
  Visceral pain is the most common reason for doctor visits in the US. Like somatic pain, virtually all visceral pain sensations begin with the activation of primary sensory neurons innervating the viscera and/or the blood vessels associated with these structures. Visceral afferents also play a central role in tissue homeostasis. Recent studies show that in addition to monitoring the state of the viscera, they perform efferent functions through the release of small molecules (e.g. peptides like CGRP) that can drive inflammation, thereby contributing to the development of visceral pathologies (e.g. diabetes Razavi, R., Chan, Y., Afifiyan, F.N., Liu, X.J., Wan, X., Yantha, J., Tsui, H., Tang, L., Tsai, S., Santamaria, P., Driver, J.P., Serreze, D., Salter, M.W., Dosch, H.M., 2006. TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes, Cell 127 1123–1135). Visceral afferents are heterogeneous with respect to their anatomy, neurochem! istry and function. They are also highly plastic in that their cellular environment continuously influences their response properties. This plasticity makes them susceptible to long-term changes that may contribute significantly to the development of persistent pain states such as those associated with irritable bowel syndrome, pancreatitis, and visceral cancers. This review examines recent insights into visceral afferent anatomy and neurochemistry and how neonatal insults can affect the function of these neurons in the adult. New approaches to the treatment of visceral pain, which focus on primary afferents, will also be discussed.
• New advances in musculoskeletal pain
  - Brain Res Rev 60(1):187-201 (2009)
  Non-malignant musculoskeletal pain is the most common clinical symptom that causes patients to seek medical attention and is a major cause of disability in the world. Musculoskeletal pain can arise from a variety of common conditions including osteoarthritis, rheumatoid arthritis, osteoporosis, surgery, low back pain and bone fracture. A major problem in designing new therapies to treat musculoskeletal pain is that the underlying mechanisms driving musculoskeletal pain are not well understood. This lack of knowledge is largely due to the scarcity of animal models that closely mirror the human condition which would allow the development of a mechanistic understanding and novel therapies to treat this pain. To begin to develop a mechanism-based understanding of the factors involved in generating musculoskeletal pain, in this review we present recent advances in preclinical models of osteoarthritis, post-surgical pain and bone fracture pain. The models discussed appear to! offer an attractive platform for understanding the factors that drive this pain and the preclinical screening of novel therapies to treat musculoskeletal pain. Developing both an understanding of the mechanisms that drive persistent musculoskeletal pain and novel mechanism-based therapies to treat these unique pain states would address a major unmet clinical need and have significant clinical, economic and societal benefits.
• Mechanisms of chronic central neuropathic pain after spinal cord injury
  - Brain Res Rev 60(1):202-213 (2009)
  Not all spinal contusions result in mechanical allodynia, in which non-noxious stimuli become noxious. The studies presented use the NYU impactor at 12.5 mm drop or the Infinite Horizons Impactor (150 kdyn, 1 s dwell) devices to model spinal cord injury (SCI). Both of these devices and injury parameters, if done correctly, will result in animals with above level (forelimb), at level (trunk) and below level (hindlimb) mechanical allodynia that model the changes in evoked somatosensation experienced by the majority of people with SCI. The sections are as follows: 1) Mechanisms of remote microglial activation and pain signaling in "below-level" central pain 2) Intracellular signaling mechanisms in central sensitization in "at-level" pain 3) Peripheral sensitization contributes to "above level" injury pain following spinal cord injury and 4) Role of reactive oxygen species in central sensitization in regional neuropathic pain following SCI. To summarize, differ! ential regional mechanisms contribute to the regional chronic pain states. We propose the importance of understanding the mechanisms in the differential regional pain syndromes after SCI in the chronic condition. Targeting regional mechanisms will be of enormous benefit to the SCI population that suffer chronic pain, and will contribute to better treatment strategies for other chronic pain syndromes.
• Descending control of nociception: Specificity, recruitment and plasticity
  - Brain Res Rev 60(1):214-225 (2009)
  The dorsal horn of the spinal cord is the location of the first synapse in pain pathways, and as such, offers a very powerful target for regulation of nociceptive transmission by both local segmental and supraspinal mechanisms. Descending control of spinal nociception originates from many brain regions and plays a critical role in determining the experience of both acute and chronic pain. The earlier concept of descending control as an "analgesia system" is now being replaced with a more nuanced model in which pain input is prioritized relative to other competing behavioral needs and homeostatic demands. Descending control arises from a number of supraspinal sites, including the midline periaqueductal gray-rostral ventromedial medulla (PAG-RVM) system, and the more lateral and caudal dorsal reticular nucleus (DRt) and ventrolateral medulla (VLM). Inhibitory control from the PAG-RVM system preferentially suppresses nociceptive inputs mediated by C-fibers, preserving! sensory-discriminative information conveyed by more rapidly conducting A-fibers. Analysis of the circuitry within the RVM reveals that the neural basis for bidirectional control from the midline system is two populations of neurons, ON-cells and OFF-cells, that are differentially recruited by higher structures important in fear, illness and psychological stress to enhance or inhibit pain. Dynamic shifts in the balance between pain inhibiting and facilitating outflows from the brainstem play a role in setting the gain of nociceptive processing as dictated by behavioral priorities, but are also likely to contribute to pathological pain states.
• Forebrain pain mechanisms
  - Brain Res Rev 60(1):226-242 (2009)
  Emotional–affective and cognitive dimensions of pain are less well understood than nociceptive and nocifensive components, but the forebrain is believed to play an important role. Recent evidence suggests that subcortical and cortical brain areas outside the traditional pain processing network contribute critically to emotional–affective responses and cognitive deficits related to pain. These brain areas include different nuclei of the amygdala and certain prefrontal cortical areas. Their roles in various aspects of pain will be discussed. Biomarkers of cortical dysfunction are being identified that may evolve into therapeutic targets to modulate pain experience and improve pain-related cognitive impairment. Supporting data from preclinical studies in neuropathic pain models will be presented. Neuroimaging analysis provides evidence for plastic changes in the pain processing brain network. Results of clinical studies in neuropathic pain patients suggest that neuroi! maging may help determine mechanisms of altered brain functions in pain as well as monitor the effects of pharmacologic interventions to optimize treatment in individual patients. Recent progress in the analysis of higher brain functions emphasizes the concept of pain as a multidimensional experience and the need for integrative approaches to determine the full spectrum of harmful or protective neurobiological changes in pain.
• Predicting therapeutic efficacy — Experimental pain in human subjects
  - Brain Res Rev 60(1):243-254 (2009)
  The pharmaceutical industry faces tough times. Despite tremendous advances in the science and technology of new lead identification and optimization, attrition rates for novel drug candidates making it into the clinic remain unacceptably high. A seamless boundary between basic preclinical and clinical arms of the discovery process, embodying the concept of 'translational research' is viewed by many as the way forward. The rational application of human experimental pain models in early clinical development is reviewed. Capsaicin, UV-irradiation and electrical stimulation methods have each been used to establish experimental hyperalgesia in Phase-I human volunteers and the application of these approaches is discussed in the context of several pharmacological examples. However, data generated from such studies must be integrated into a well-conceived and executed series of Phase-II efficacy trials in patients in order to derive maximal benefit. The challenges involved! in optimal Phase-II/III trial design are reviewed with specific attention to the issues of sample size and placebo response. Finally, the application and potential of cortical EEG studies are discussed as an objective alternative to more conventional pain assessment tools with specific examples of how this technique has been applied to the study of NSAID and opiate-based therapeutics.
• Targeting CB2 receptors and the endocannabinoid system for the treatment of pain
  - Brain Res Rev 60(1):255-266 (2009)
  The endocannabinoid system consists of the cannabinoid (CB) receptors, CB1 and CB2, the endogenous ligands anandamide (AEA, arachidonoylethanolamide) and 2-arachidonoylglycerol (2-AG), and their synthetic and metabolic machinery. The use of cannabis has been described in classical and recent literature for the treatment of pain, but the potential for psychotropic effects as a result of the activation of central CB1 receptors places a limitation upon its use. There are, however, a number of modern approaches being undertaken to circumvent this problem, and this review represents a concise summary of these approaches, with a particular emphasis upon CB2 receptor agonists. Selective CB2 agonists and peripherally restricted CB1 or CB1/CB2 dual agonists are being developed for the treatment of inflammatory and neuropathic pain, as they demonstrate efficacy in a range of pain models. CB2 receptors were originally described as being restricted to cells of immune origin, but t! here is evidence for their expression in human primary sensory neurons, and increased levels of CB2 receptors reported in human peripheral nerves have been seen after injury, particularly in painful neuromas. CB2 receptor agonists produce antinociceptive effects in models of inflammatory and nociceptive pain, and in some cases these effects involve activation of the opioid system. In addition, CB receptor agonists enhance the effect of μ-opioid receptor agonists in a variety of models of analgesia, and combinations of cannabinoids and opioids may produce synergistic effects. Antinociceptive effects of compounds blocking the metabolism of anandamide have been reported, particularly in models of inflammatory pain. There is also evidence that such compounds increase the analgesic effect of non-steroidal anti-inflammatory drugs (NSAIDs), raising the possibility that a combination of suitable agents could, by reducing the NSAID dose needed, provide an efficacious treatment stra! tegy, while minimizing the potential for NSAID-induced gastroi! ntestinal and cardiovascular disturbances. Other potential "partners" for endocannabinoid modulatory agents include α2-adrenoceptor modulators, peroxisome proliferator-activated receptor α agonists and TRPV1 antagonists. An extension of the polypharmacological approach is to combine the desired pharmacological properties of the treatment within a single molecule. Hopefully, these approaches will yield novel analgesics that do not produce the psychotropic effects that limit the medicinal use of cannabis.
• Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks
  - Brain Res Rev 60(1):267-277 (2009)
  The vanilloid receptor TRPV1 is a homotetrameric, non-selective cation channel abundantly expressed in the nociceptors (c-fibers). TRPV1 is considered as a highly validated pain target because, i) its agonists such as capsaicin cause desensitization of TRPV1 channels that relieves pain behaviors in preclinical species, and ii) its antagonists relieve pain behaviors in rodent models of inflammation, osteoarthritis, and cancer. Hence, both agonists and antagonists of TRPV1 are being evaluated as potential analgesics in clinical trials. Clinical trial results of TRPV1 agonists such as resiniferatoxin in interstitial cystitis, NGX 4010 in post-herpetic neuralgia, and 4975 (Adlea™) in osteoarthritis, bunionectomy, and Morton's neuroma have been reported. Similarly, clinical trial results of TRPV1 antagonists such as SB-705498 and AMG 517 have also been published recently. Overall, some molecules (e.g., capsaicin) demonstrated potential analgesia in certain conditions (pos! tsurgical pain, postherpetic neuralgia, pain in diabetic neuropathy, osteoarthritis, bunionectomy, and Morton's neuroma), whereas others fell out of the clinic due to on-target liabilities or failed to demonstrate efficacy. This review summarizes recent advances and setbacks of TRPV1 agonists and antagonists in the clinic and predicts future directions.