Bidirectional modulation of windup by NMDA receptors in the rat spinal trigeminal nucleus

Activation of afferent nociceptive pathways is subject to activity-dependent plasticity, which may manifest as windup, a progressive increase in the response of dorsal horn nociceptive neurons to repeated stimuli. At the cellular level, N-methyl-d-aspartate (NMDA) receptor activation by glutamate released from nociceptive C-afferent terminals is currently thought to generate windup. Most of the wide dynamic range nociceptive neurons that display windup, however, do not receive direct C-fibre input. It is thus unknown where the NMDA mechanisms for windup operate. Here, using the Sprague-Dawley rat trigeminal system as a model, we anatomically identify a subpopulation of interneurons that relay nociceptive information from the superficial dorsal horn where C-fibres terminate, to downstream wide dynamic range nociceptive neurons. Using in vivo electrophysiological recordings, we show that at the end of this pathway, windup was reduced (24 +/- 6%, n = 7) by the NMDA receptor antagonist AP-5 (2.0 fmol) and enhanced (62 +/- 19%, n = 12) by NMDA (1 nmol). In contrast, microinjections of AP-5 (1.0 fmol) within the superficial laminae increased windup (83 +/- 44%, n = 9), whereas NMDA dose dependently decreased windup (n = 19).These results indicate that NMDA receptor function at the segmental level depends on their precise location in nociceptive neural networks. While some NMDA receptors actually amplify pain information, the new evidence for NMDA dependent inhibition of windup we show here indicates that, simultaneously, others act in the opposite direction. Working together, the two mechanisms may provide a fine tuning of gain in pain.     

Number magnitude and grip aperture interaction

Behavioural, neuropsychological and functional imaging studies suggest possible interactions between number processing and finger representation. Since grasping requires the object size to be estimated in order to determine the appropriate hand shaping, coding number magnitude and grasping may share common processes. In the present study, participants performed either a grip closure or opening depending on the parity of a visually presented digit. Electromyographic recordings revealed that grip closure was initiated faster in response to small digit presentation whereas grip opening was initiated faster in response to large digits. This result was interpreted in reference to a recent theory which proposed that physical and numerical quantities are represented by a generalized magnitude system dedicated to action.     

Texture analysis of the brain: from animal models to human applications

Magnetic resonance imaging (MRI) is widely used to image brain in vivo both in studies in animal models and for human diagnosis. A large part of the value of MRI is due to the fact that soft tissue contrast is enhanced by the substantial variation in the T(1) and T(2) relaxation times between tissues. It may be possible to use an alternative approach, which does not rely on the absolute measurement of relaxation times. Generally speaking, textures are complex visual patterns composed of entities, or subpatterns, that have characteristic brightness, color, slope, size, etc. Thus, texture can be regarded as a similarity grouping in an image. The properties of the local subpattern give rise to the perceived lightness, uniformity, density, roughness, regularity, linearity, frequency, phase, directionality, coarseness, randomness, fineness, smoothness, and granulation. The purpose here is to illustrate how texture analysis can be used in animal models and in human clinical applications, as well as in the search for further pharmacological applications in humans. Thus, this article summarzes three different MRI studies in (i) rats, using the lipocarpine epileptic rat model as an animal model; (ii) patients with Alzheimer's disease; and (iii) patients with schizophrenia.     

Specific alteration of the expression of selected hypothalamic neuropeptides during acute and late mouse brain infection using a morbillivirus: relevance to the late-onset obesity?

Neurotropic viruses are involved in pathologies of the central nervous system, triggering transient or irreversible disorders, such as neurological diseases or homeostasis imbalance. In experimental animals, viruses have been shown to cause obesity, a complex disease depending on multiple factors, including genetic susceptibility and environmental components. Using a mouse model of virally induced obesity following brain infection by the Canine Distemper Virus (CDV), a morbillivirus closely related to the human measles virus, we investigated the modulation of expression of several hypothalamic neuropeptides known to intervene in the regulation of body weight and energy expenditure, both during the acute and late stages of infection. During the acute stage, while viral replication occurs, we found a dramatic decrease of expressions of neuropeptides, in particular neuropeptide Y, melanin-concentrating hormone (MCH), hypocretin, vasopressin and tachykinins, the magnitude of which seemed to be linked to the viral burden and the individual susceptibility. The effect of the virus, however, varied with the hypothalamic nucleus and neuropeptide involved, suggesting that certain circuits were affected while others remained intact. During the late stage of infection, marked recovery to the initial hypothalamic levels of peptide expression was seen in a number of lean animals, suggesting recovery of homeostasis equilibrium. Interestingly, some neuropeptidergic systems remained disturbed in mice exhibiting obese phenotype, arguing for their involvement in triggering/maintaining obesity. Even though our data could not fully explain the viral-induced obesity, they may be helpful in understanding the molecular events associated with obesity and in investigating therapeutic alternatives.     

Role of tissue-derived plasminogen activator (t-PA) in an excitotoxic mouse model of neonatal white matter lesions

White matter (WM) lesions in preterm newborns may lead to cerebral palsy. To study WM lesions in a mouse model, we used intrapallial stereotactic injections of ibotenic acid, an N-methyl-D-aspartate receptor agonist. Previous studies support a contribution of tissue-type plasminogen activator (t-PA) to the brain lesions seen in various adult excitotoxic models. Therefore, we studied both 5-day-old (P5) wild-type mice and t-PA knock-out (t-PA-/-) mice. The ibotenic acid doses required to induce WM cysts were lower in the wild-type mice (EC50 < 0.01 microg/animal) than in the t-PA-/- mice (EC50 = 2.5 microg/animal) (p < 0.01), indicating the existence of t-PA-dependent and t-PA-independent mechanisms. Dose-dependent prolonged cyst growth occurred in the wild-type mice only. Early microglial activation and astrogliosis were similar in the wild-type and t-PA-/- mice. In adult mice (P45), demyelination occurred at the injection site in both groups but the astroglial scar was denser in the wild-type than in the t-PA-/- mice. These data support involvement of t-PA at several stages of WM lesion formation. Inactivation of t-PA might confer protection by prolonged hemostasis. The role of t-PA in cyst expansion suggests a new approach to the development of neuroprotective strategies in infants with developing WM lesions.     

In vivo imaging of cardiovascular endothelin receptors using the novel radiolabelled antagonist [18F]-SB209670 and positron emission tomography (microPET)

The aim of this study was to develop an F-labelled analogue of SB209670 with subnanomolar affinity for the endothelin receptor and to test whether it would have the required pharmacokinetic properties to permit binding and imaging of endothelin receptors in rat heart in vivo using small animal positron emission tomography (PET) imaging. [18F]-SB209670 could be produced in a total radiochemical yield of 14.9 +/- 3.8% in 162 +/- 7 minutes (n = 6). The radiochemical purity of the isolated radioligand was 99% and the specific activity was 100-150 GBq/micromol. In vitro characterization using ligand-binding assays demonstrated that [18F]-SB209670 bound with a single subnanomolar affinity to human heart tissue (n = 3) with a KD = 0.67 +/- 0.14 nM and a Bmax = 168.3 +/- 29.3 fmol/mg protein. The binding was time-dependent with a half-time (t(1/2)) for association of 3.8 minutes and an association rate constant (kobs) of 0.182 +/- 0.032/min. In vivo distribution in the rat was studied using microPET. Dynamic imaging revealed a fast clearance of [F]-SB209670 from the circulation by the liver, indicative of a high degree of metabolism. However, visualization of uptake in the rat heart was achievable and dynamic PET data together with the in vitro results suggest that [F]-SB209670 binds rapidly and primarily to endothelin-A receptors in the heart.     

The effects of decanted sediments on embryogenesis in oysters (Crassostrea gigas)

Sediments act as sinks for contaminants of natural and anthropogenic origin, constituting a risk to the living organisms. In this study, sediments were collected from three sites on the coast of southwest France. The objective of this research was to determine the effects of sediments on embryonic development of bivalves and to identify precisely when the contaminants affect the embryos and induce them to develop in an abnormal way. The toxicity of decanted sediments and overlying waters were assessed using the oyster embryo bioassay. The physical characteristics and contaminant levels in the sediments were measured, including polycyclic aromatic hydrocarbon (PAH) and metal concentrations. Despite contaminant concentrations for PAH and metals only exceeding the effects range-low levels, all decanted sediments tested induced deleterious effects on the embryonic development of oysters, while no significant abnormalities were observed for overlying waters. The study results suggest that abnormal larvae mainly are caused by direct contact with contaminated sediments.