The ability to control cell volume is pivotal for cell function. Cell volume perturbation elicits a wide array of signaling events, leading to protective (e.g., cytoskeletal rearrangement) and adap...

Physiology of cell volume regulation in vertebrates.

Hyponatraemia, defined as a serum sodium concentration !135 mmol/l, is the most common disorder of body fluid and electrolyte balance encountered in clinical practice. It can lead to a wide spectrum of clinical symptoms, from subtle to severe or even life threatening, and is associated with increased mortality, morbidity and length of hospital stay in patients presenting with a range of conditions. Despite this, the management of patients remains problematic. The prevalence of hyponatraemia in widely different conditions and the fact that hyponatraemia is managed by clinicians with a broad variety of backgrounds have fostered diverse institution- and speciality-based approaches to diagnosis and treatment. To obtain a common and holistic view, the European Society of Intensive Care Medicine (ESICM), the European Society of Endocrinology (ESE) and the European Renal Association – European Dialysis and Transplant Association (ERA–EDTA), represented by European Renal Best Practice (ERBP), have developed the Clinical Practice Guideline on the diagnostic approach and treatment of hyponatraemia as a joint venture of three societies representing specialists with a natural interest in hyponatraemia. In addition to a rigorous approach to methodology and evaluation, we were keen to ensure that the document focused on patient-important outcomes and included utility for clinicians involved in everyday practice.

/pdf/clinical-practice-guideline-on-diagnosis-and-treatment-of-509w3449ob.pdf

Clinical practice guideline on diagnosis and treatment of hyponatraemia

The clinical use of TRPV1 (transient receptor potential vanilloid subfamily, member 1; also known as VR1) antagonists is based on the concept that endogenous agonists acting on TRPV1 might provide a major contribution to certain pain conditions. Indeed, a number of small-molecule TRPV1 antagonists are already undergoing Phase I/II clinical trials for the indications of chronic inflammatory pain and migraine. Moreover, animal models suggest a therapeutic value for TRPV1 antagonists in the treatment of other types of pain, including pain from cancer. We argue that TRPV1 antagonists alone or in conjunction with other analgesics will improve the quality of life of people with migraine, chronic intractable pain secondary to cancer, AIDS or diabetes. Moreover, emerging data indicate that TRPV1 antagonists could also be useful in treating disorders other than pain, such as urinary urge incontinence, chronic cough and irritable bowel syndrome. The lack of effective drugs for treating many of these conditions highlights the need for further investigation into the therapeutic potential of TRPV1 antagonists.

The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept

Sensory neurons innervating the skin encode the familiar sensations of temperature, touch and pain. An explosion of progress has revealed unanticipated cellular and molecular complexity in these senses. It is now clear that perception of a single stimulus, such as heat, requires several transduction mechanisms. Conversely, a given protein may contribute to multiple senses, such as heat and touch. Recent studies have also led to the surprising insight that skin cells might transduce temperature and touch. To break the code underlying somatosensation, we must therefore understand how the skin's sensory functions are divided among signalling molecules and cell types.

https://www.maths.gla.ac.uk/~rs/res/BladderNerve/00SAC-Limpkin.pdf

Mechanisms of sensory transduction in the skin

Systemic osmoregulation is a vital process whereby changes in plasma osmolality, detected by osmoreceptors, modulate ingestive behaviour, sympathetic outflow and renal function to stabilize the tonicity and volume of the extracellular fluid. Furthermore, changes in the central processing of osmosensory signals are likely to affect the hydro-mineral balance and other related aspects of homeostasis, including thermoregulation and cardiovascular balance. Surprisingly little is known about how the brain orchestrates these responses. Here, recent advances in our understanding of the molecular, cellular and network mechanisms that mediate the central control of osmotic homeostasis in mammals are reviewed.

http://www.med.uottawa.ca/courses/nsc5104/assets/documents/dr_renaud2009/nrn2400.pdf

Central mechanisms of osmosensation and systemic osmoregulation.

Body fluid homeostasis requires the release of arginine-vasopressin (AVP, an antidiuretic hormone) from the neurohypophysis. This release is controlled by specific and highly sensitive 'osmoreceptors' in the hypothalamus. Indeed, AVP-releasing neurons in the supraoptic nucleus (SON) are directly osmosensitive, and this osmosensitivity is mediated by stretch-inhibited cation channels. However, the molecular nature of these channels remains unknown. Here we show that SON neurons express an N-terminal splice variant of the transient receptor potential vanilloid type-1 (Trpv1), also known as the capsaicin receptor, but not full-length Trpv1. Unlike their wild-type counterparts, SON neurons in Trpv1 knockout (Trpv1−/−) mice could not generate ruthenium red–sensitive increases in membrane conductance and depolarizing potentials in response to hyperosmotic stimulation. Moreover, Trpv1−/− mice showed a pronounced serum hyperosmolality under basal conditions and severely compromised AVP responses to osmotic stimulation in vivo. These results suggest that the Trpv1 gene may encode a central component of the osmoreceptor.

An N-terminal variant of Trpv1 channel is required for osmosensory transduction

Intra-articularly injected complete Freund's adjuvant creates in rats a chronic monoarthritis suitable for studying neuronal plasticity and chronic pain. Using such a model, we report electrophysiological and morphological evidence of alterations in somatosensory synaptic function. In arthritic rats, the baseline activity of dorsal spinal cord wide dynamic range or nociceptive-specific neurons was greater than in control animals. Moreover, neuronal responses elicited by an innocuous stimulation with von Frey filaments applied to the arthritic joint were greater in amplitude and produced the afterdischarge that normally characterizes a nociceptive response. In contrast to the response in control animals, passive movement of the arthritic joint produced an increase in the amplitude of the response of these neurons to iontophoretic application of glutamate receptor agonists over a time frame of 10-30 min. This potentiation was blocked by pretreatment with a neurokinin-1 (NK-1) receptor antagonist, suggesting the involvement of substance P. Ultrastructural analysis of the dorsal horn revealed that movement of the arthritic joint also induced NK-1 receptor internalization, indicative of nociception. Morphological examination revealed significantly increased expression of substance P and its receptor within the superficial dorsal horn of monoarthritic animals. These unique functional and chemical changes reflect alterations in both presynaptic and postsynaptic mechanisms in nociceptive transmission at the spinal level. Thus, although treatment of arthritis should obviously target its peripheral aetiology, targeting its central components is a logical therapeutic complementary objective.

/pdf/remodelling-of-spinal-nociceptive-mechanisms-in-an-animal-o3vi0v4zu0.pdf

Remodelling of spinal nociceptive mechanisms in an animal model of monoarthritis

1035 M/S n° 12, vol. 22, décembre 2006 > Il y a plus de cent ans Claude Bernard énonçait que la « fixité du milieu intérieur » était une condition nécessaire à la « vie libre et indépendante » [1]. Tel qu’il l’avait anticipé, il est maintenant établi que la plupart des mécanismes homéostatiques ont pour but essentiel de maintenir la constance des paramètres physico-chimiques des fluides corporels. La pression osmotique du sérum, représentant la concentration des substances dissoutes dans le sang, figure de façon proéminente parmi les paramètres les plus fortement défendus par l’organisme. Les déviations aiguës et significatives (> 10%) de l’osmolarité sanguine entraînent des changements du volume cérébral qui peuvent provoquer une progression de désordres neurologiques : migraine, confusion, convulsions, coma qu’un produit du gène codant pour le canal ionique transient receptor potential vanilloid (TRPV) de type 1 (TRPV1) est nécessaire pour installer le processus de transduction des osmorécepteurs cérébraux et pour susciter l’activation de la soif et de la libération de vasopressine.

/pdf/les-trpv-des-canaux-qui-vous-donnent-soif-2y03kzql3j.pdf

Reza Sharif Naeini

Papers

An N-terminal variant of Trpv1 channel is required for osmosensory transduction

Remodelling of spinal nociceptive mechanisms in an animal model of monoarthritis

Les TRPV, des canaux qui vous donnent soif !