Neuropathic pain

The putative anti-inflammatory and anti-nociceptive activity of the heptapeptide somatostatin analogue TT-232 (D-Phe-Cys-Tyr-D-Thr-Lys-Cys-Thr-NH 2 ) was investigated in the rat and mouse, as well as its effect on neuropathic hyperalgesia, gastric ulceration and the release of sensory neuropeptides. In the rat, carrageenin-induced paw oedema was inhibited dose dependently by TT-232 (3×2.5-20 µg/kg i.v.). Evans blue accumulation induced by intraarticular bradykinin injection (0.5 nmol in 0.1 ml) was slightly, but significantly inhibited by a single TT-232 dose (5-20 µg/kg). Cutaneous neutrophil accumulation over a 3-h period after intradermal (i.d.) injection of carrageenin (1 mg/site) or interleukin 1β (IL-1β, 3 pmol/ site) was inhibited significantly by TT-232 (3×80 µg/kg i.v.), while diclofenac (3×10 mg/kg i.v.) elicited significant inhibition only in the IL-1β test. In the mouse, TT-232 potently decreased oedema formation induced by 2.5% capsaicin applied topically to the ear. Mechano-nociception in the rat hind-paw during neuropathic pain induced by partial sciatic nerve injury (model of Seltzer) was measured using the Randall-Selitto test. TT-232 (5-20 µg/kg i.p. on the 7th day after the operation) dose-dependently inhibited the mechano-nociceptive hyperalgesia. In vitro release of substance P (SP), calcitonin gene-related peptide (CGRP) and somatostatin from the isolated rat trachea in response to electrical field stimulation (40 V, 0.1 ms, 10 Hz, 120 s) of its nervous elements was inhibited sig-nificantly by 500 nM TT-232. The role of G protein-coupled receptors in the effect of TT-232 was indicated by the prevention of its inhibitory action on the release of sensory neuropeptides by incubation the tissue for 1 or 6 h with pertussis toxin (100 ng/ml). The release of sensory neuropeptides to in response to electrical nerve stimulation was not inhibited by a potent tyrosine kinase inhibitor, genistein (50 µM). TT-232 (up to 5 mg/kg i.p.) did not induce mucosal lesions in either the stomach or the duodenum.

During the past two decades, many pharmacological strategies have been investigated for the management of painful neuropathies. However, neuropathic pain still remains a clinical challenge. A combination of therapies is often required, but unfortunately in most cases adequate pain relief is not achieved. Recently, attention has been focused on the physiological and pharmacological effects of L-acetylcarnitine in neurological disorders. There are a number of reports indicating that L-acetylcarnitine can be considered as a therapeutic agent in neuropathic disorders including painful peripheral neuropathies. In this review article, we will examine the antinociceptive and the neuroprotective effects of Lacetylcarnitine as tested in clinical studies and in animal models of nerve injury.

This review examines recent preclinical research on toxic peripheral neuropathy and potential therapeutic developments. Chemotherapy-induced peripheral neurotoxicity is a major clinical problem because it represents the dose-limiting side effects of a significant number of antineoplastic drugs. Patients are unable to complete full or optimal treatment schedules. The incidence of chemotherapy-induced peripheral neuropathy varies depending on the drugs and schedules used, and this can be quite high, particularly when neurophysiological methods are used to make a diagnosis. However, even when chemotherapy-induced peripheral neuropathy is not a doselimiting side effect, its onset may severely affect the quality of life of cancer patients and cause chronic discomfort. As such, improved understanding of the pathophysiology of chemotherapy-induced neurotoxicity need for animal models is clinically relevant and will assist in the development of future neuroprotective strategies and also in the design of novel chemotherapies with improved toxicity profiles. In this review, the features of animal models of chemotherapy-induced painful neuropathy developed for 20 years, due to the administration of the most widely used drugs, such as platinum drugs, taxanes, and vinca alkaloids, will be discussed. In a second part, data available on neuroprotectants and treatment strategies, evaluated using these previous animal models in the attempt to prevent neuropathic pain, will be summarized.

Biological, genetic, and clinical evidence provide validation for N-type calcium channels (Ca V 2.2) as therapeutic targets for chronic pain. A state-dependent Ca V 2.2 inhibitor may provide an improved therapeutic window over ziconotide, the peptidyl Ca V 2.2 inhibitor used clinically. Supporting this notion, we recently reported that in preclinical models, the state-dependent Ca V 2 inhibitor (3R)-5-(3-chloro-4fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one (TROX-1) has an improved therapeutic window compared with ziconotide. Here we characterize TROX-1 inhibition of Cav2.2 channels in more detail. When channels are biased toward open/inactivated states by depolarizing the membrane potential under voltage-clamp electrophysiology, TROX-1 inhibits Ca V 2.2 channels with an IC 50 of 0.11 M. The voltage dependence of Ca V 2.2 inhibition was examined using automated electrophysiology. TROX-1 IC 50 values were 4.2, 0.90, and 0.36 M at Ϫ110, Ϫ90, and Ϫ70 mV, respectively. TROX-1 displayed usedependent inhibition of Ca V 2.2 with a 10-fold IC 50 separation between first (27 M) and last (2.7 M) pulses in a train. In a fluorescence-based calcium influx assay, TROX-1 inhibited Ca V 2.2 channels with an IC 50 of 9.5 M under hyperpolarized conditions and 0.69 M under depolarized conditions. Finally, TROX-1 potency was examined across the Ca V 2 subfamily. Depolarized IC 50 values were 0.29, 0.19, and 0.28 M by manual electrophysiology using matched conditions and 1.8, 0.69, and 1.1 M by calcium influx for Ca V 2.1, Ca V 2.2, and Ca V 2.3, respectively. Together, these in vitro data support the idea that a state-dependent, non-subtype-selective Ca V 2 channel inhibitor can achieve an improved therapeutic window over the relatively state-independent Ca V 2.2-selective inhibitor ziconotide in preclinical models of chronic pain.

This Atlas is the result of research about 3142 patients recruited prospectively and consecutively since 2004. As the clinic gives us opportunity to observe many more Aβ axonal lesions (axonotmesis) than transections (neurotmesis), the mapped hypoaesthetic territories are partial. The Authors, therefore, defined, for each cutaneous nerve branch, the autonomous territory and the boundary markers of the largest territory of cutaneous origin. Each anatomical plate of a cutaneous branch is the superposition of tens, even hundreds of observations seen in clinical practice - 3133 maps of cutaneous hypoaesthetic territories observed. We also cross-referenced these with data published in 99 anatomy books.

This 1st English edition - stemming from the previous 3rd French edition published by Sauramps Médical - illustrates the usefulness of anatomical knowledge for clinical practice.

Leg pain is a frequent accompaniment to low back pain, arising from disorders of neural or musculoskeletal structures of the lumbar spine. Differentiating between different sources of radiating leg pain is important to make an appropriate diagnosis and identify the underlying pathology. It is proposed that low back-related leg pain be divided into four subgroups according to the predominating pathomechanisms involved. The first subgroup features central sensitization with mainly positive symptoms such as hyperalgesia, the second subgroup involves denervation with significant axonal damage showing predominantly negative sensory symptoms and possibly motor loss and the third subgroup involves peripheral nerve sensitization with enhanced nerve trunk mechanosensitization. The fourth subgroup features somatic referred pain from musculoskeletal structures, such as the intervertebral disc or facet joints. Accordingly, four groups of patients with leg pain associated with structures in the lower back can be identified:

Neuropathic pain is a chronic pain state that develops a central component following acute nerve injury. However, the pathogenic mechanisms involved in the expression of this central component are not completely understood. We have investigated the role of Ž . brain-associated TNF in the evolution of hyperalgesia in the chronic constriction injury CCI model of neuropathic pain. Thermal Ž . nociceptive threshold has been assessed in rats male, Sprague-Dawley that have undergone loose, chromic gut ligature placement Ž . around the sciatic nerve. Total levels of TNF in regions of the brain, spinal cord and plasma have been assayed WEHI-13VAR bioassay . Bioactive TNF levels are elevated in the hippocampus. During the period of injury, hippocampal noradrenergic neurotransmission Ž . demonstrates a decrease in stimulated norepinephrine NE release, concomitant with elevated hippocampal TNF levels. Continuous Ž . Ž . intracerebroventricular i.c.v. microinfusion of TNF-antibodies Abs starting at four days, but not six days, following ligature placement completely abolishes the hyperalgesic response characteristic of this model, as assessed by the 588C hot-plate test. Antibody infusion does not decrease spinal cord or plasma levels of TNF. Continuous i.c.v. microinfusion of rrTNFa exacerbates the hyperalgesic response by ligatured animals, and induces a hyperalgesic response in animals not receiving ligatures. Likewise, field-stimulated hippocampal adrenergic neurotransmission is decreased upon continuous i.c.v. microinfusion of TNF. These results indicate an important role of brain-derived TNF, both in the pathology of neuropathic pain, as well as in fundamental pain perception. q

Title. The impact of neuropathic pain on relationships.Aim.  This paper is a report of a study exploring the impact of neuropathic pain on family, social and working relationships among patients at a pain clinic serving a large urban area.Background.  Neuropathic pain is a particularly distressing type of chronic pain which is extremely difficult to manage successfully. It produces a range of unpleasant symptoms and adversely affects patients’ quality of life, but little is known about its personal impact.Method.  A descriptive and exploratory approach was used and 10 participants participated in three focus groups in 2005. Because of the low response rate of 20% from the initial sample, a second sample of 16 patients was invited to participate. However, only one person responded and therefore it was not possible to convene an additional group.Findings.  The unpleasant and bizarre nature of neuropathic pain underpinned much of its impact in terms of respondents’ difficulties in maintaining a range of relationships. For closer relationships, key difficulties centred on the reduction in quality and/or number of personal relationships. For more distant relationships and those with professionals, frustration at the invisibility of their pain and their own failure to communicate symptoms and its consequences were central.Conclusion.  More extensive work is needed to improve our understanding of how neuropathic pain is experienced, how it affects close and more distant kinds of relationships, and how healthcare professionals might best support people with persistent neuropathic pain to maintain personal and social relationships, and to communicate their pain effectively.

Ce manuel est destiné aux rééducateurs, aux médecins généralistes et de toutes les spécialités, ainsi qu’aux patients qui cherchent désespé-rément une solution à leur douleur.

La méthode de rééducation sensitive diminue les douleurs neuropa-thiques depuis la peau partiellement engourdie ou hypersensible au tou-cher. La peau, qui est le plus grand organe du corps humain, est fréquemment soumise à des traumatismes qui provoquent de micro lésions nerveuses avec leur cortège de symptômes : des sensations de brûlures « comme un coup de soleil » ou « comme un feu à l’intérieur », des douleurs au caractère électrique « irradiations » ou « élancements », des fourmillements, par exemples. Cette méthode est basée sur la plasticité neuronale du systême neurologique somesthé-sique – des yeux de la peau vers le cerveau – qui permet de modifier la situation, même plus de vingt mois après la lésion.

Cette méthode, qui a 15 ans, est aujourd’hui encyclopédique et de re-nommée mondiale. Les thérapeutes qui la pratiquent dans 29 pays sont organisés en un Réseau de Rééducation Sensitive de la Douleur (RRSD) neuropain.ch, qui décerne le titre de Rééducatrice/teur Sensi-tive/tif de la Douleur Certifié(e) (RSDC®).

« Ce manuel va permettre de stimuler tous les professionnels de la santé qui se consacrent à la gestion de la douleur et aux problèmes qui y sont associés. »        Ronald Melzack, McGill University, Montréal.