1,721,059 research outputs found
Antinociceptive effects of lacosamide on spinal neuronal and behavioural measures of pain in a rat model of osteoarthritis.
No full textAlterations in voltage-gated sodium channel (VGSC) function have been linked to chronic pain and are good targets for analgesics. Lacosamide (LCM) is a novel anticonvulsant that enhances the slow inactivation state of VGSCs. This conformational state can be induced by repeated neuronal firing and/or under conditions of sustained membrane depolarisation, as is expected for hyperexcitable neurones in pathological conditions such as epilepsy and neuropathy, and probably osteoarthritis (OA). In this study, therefore, we examined the antinociceptive effect of LCM on spinal neuronal and behavioural measures of pain, in vivo, in a rat OA model
Monoaminergic control of the central processing of sensory stimuli in a rat model of osteoarthritis
No full textThe main symptom of osteoarthritis (OA) is chronic pain. In many cases, this pain can be explained by stimulation of sensitised nociceptors in the joint, however changes in central nociceptive processing may also feature. These studies used single-unit recordings in the deep dorsal-horn and behavioural analysis to examine whether central sensitisation and changes in descending serotonergic (5-HT) and noradrenergic (NA) inhibition are features of the monosodium iodoacetate model of OA pain. Central sensitisation was indicated by the presence of both behavioural and spinal neuronal hypersensitivity in both an early- and a late-phase of the model .The early-phase was characterised by an increased descending noradrenergic inhibition, indicated by excitatory effects from the α2-adrenoceptor antagonist atipamezole on evoked neuronal activity, which was lost in the late-phase of the model. In the late-phase, excitatory effects of the 5-HT7 receptor antagonist SB-269970 suggested an increased descending serotonergic inhibition. In each phase, systemic injection of the 5-HT/NA reuptake inhibitor milnacipran reduced behavioural and neuronal measures of central sensitisation. In naïve animals and the early-phase of the model, these effects were mediated by NA acting at spinal α2 adrenoceptors. In the late-phase, spinal α2 adrenoceptors did not contribute to the effects of milnacipran, and 5-HT acting at spinal 5-HT7 receptors was better able to explain some of this neuronal inhibition. These studies suggest central sensitisation and altered descending monoaminergic inhibition of nociceptive processing are present in this model of OA pain. Such alterations in CNS function accord with signs of central sensitisation and dysregulated descending inhibition seen in clinical studies and might foreshadow the development of pain in OA. Additionally, the use of milnacipran, whose mechanism of action comes via a modulation of descending monoaminergic inhibition, may control centrally-mediated OA pain, though the mechanisms by which it acts appears dependent on basal activity in these pathways
Electrophysiological characterisation of neuronal components of cold sensitivity
No full textAberrant cold sensitivity is apparent in several neuropathies of peripheral and central origin, and is poorly treated by currently available drugs. In an attempt to understand the mechanisms of cold evoked hyperalgesia and analgesia, these studies examined the dual pro- and anti-nociceptive roles of TRPM8, a cold temperature gated channel, and the role of calcium channels within cold sensitive pathways through a combination of in vivo electrophysiology, behavioural measures and gene ablation. Blocking TRPM8 with novel antagonists revealed lamina V/VI neuronal responses to innocuous and noxious cold stimulation were conserved in naïve rats. However, under neuropathic conditions inhibition of TRPM8 decreased neuronal responses to innocuous and noxious cold stimuli. This corresponded with an attenuation of behavioural hypersensitivity to innocuous cooling. Remarkably, systemically activating TRPM8 with a novel agonist resulted in identical neuronal and behavioural effects in neuropathic rats. Menthol is known to relieve various pain conditions as well as inducing hyperalgesia. Unlike in human subjects, menthol fails to induce central sensitisation in naïve rats, whereas in neuropathic rats topical menthol exerts some similar effects to the systemically dosed TRPM8 agonist. Gene ablation identifies a role of α2δ-1, an auxiliary calcium channel subunit, in cold and mechanical sensory pathways, likely dependent on impaired trafficking of calcium channels. Furthermore, α2δ-1 knockout mice exhibit a delay in the development of neuropathic like behaviours after injury. In neuropathic rats, systemic and spinal delivery of an activation state dependent Cav2 antagonist suppresses neuronal responses to mechanical stimuli but reveals no change in channel function within cold sensitive pathways. These findings expand the understanding of the neural basis of cold sensitivity and demonstrate TRPM8 is not essential to all forms of cold transduction in naïve rats, and that both inhibiting and activating TRPM8 have similar selective modality related inhibitory effects on cold transduction in neuropathic rats
The processing of inflammatory joint pain in the developing spinal cord
Full text linkApproximately 10 in 100,000 children develop inflammatory arthritis every year and a large proportion of those are diagnosed as having Juvenile Idiopathic Arthritis (JIA). A major cause of suffering in the disease is pain, and indeed it contributes significantly to the morbidity of this condition when assessed by various disability scores. Pain from affected joints causes sleep disturbance, limits normal activities, disrupts school attendance and results in considerable psychosocial stress. Very little is understood about arthritic pain processing in the immature nervous system. Both clinical and neurobiological studies in animal models show that CNS nociceptive connections differ in juveniles and adults and that the normal maturation of these connections depends upon early life stress and pain experience. The immaturity of synaptic connections and integrated circuits means that children’s pain experience is different from that of adults and may impact upon pain in later life. It was our aim to develop and characterise a rodent model of joint inflammation to better understand the neurobiological basis of joint pain in early life and to establish whether joint inflammation in childhood influences joint pain sensitivity as an adult. In the first results chapter (Chapter 2), the normal development of joint evoked and cutaneous reflexes were mapped out over the postnatal period. In the second Results chapter (Chapter 3), monoarthritis of the ankle was induced in Sprague-Dawley rats of different postnatal ages using complete Freund’s adjuvant (CFA) and the effect of this inflammation upon spinal circuits was studied using behavioural and electrophysiological measures. Electromyographic (EMG) recordings show that inflammation leads to widespread reflex hypersensitivity to mechanical stimuli in young animals that differs significantly from the effects of adult joint inflammation. In adults, a significant attenuation of reflexes, or ‘protective inhibition’ phase was observed at 24 hours and 4 days post-inflammation, followed by a ‘hypersensitivity phase’ at 10 days when reflexes to pinch were dramatically enhanced. These effects were not detected with simple behavioural observation. In the third results chapter (Chapter 4), the long-term effects of joint inflammation (6 weeks) were investigated and shown to be highly dependent upon the age at which the inflammation occurred. Baseline nociceptive reflexes were enhanced in animals that had experienced joint inflammation when young (postnatal day (P) 8) but slightly reduced if the inflammation had occurred at the same time interval, but in adult life. The effects of a second injury in adulthood also depended on the past history of the animal. Animals first inflamed in early life, displayed a significantly greater ‘protective inhibition’ than adult inflamed controls, while animals first inflamed in adult life displayed enhanced hypersensitivity to joint inflammation. The results here describe previously unknown characteristics and mechanisms of joint pain in early life which will contribute to a better understanding and treatment of pain in JIA
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
ANTAGONISM AT THE GLYCINE SITE ON THE NMDA RECEPTOR REDUCES SPINAL NOCICEPTION IN THE RAT
No full textThe effects of 7-chlorokynurenate (7CK), an antagonist at the allosteric glycine site associated with the N-methyl-D-aspartate receptor, applied intrathecally, were tested on nociceptive neurons in the dorsal horn of the anaesthetized rat. 7CK reduced the frequency dependent potentiation (wind-up) of the cells to repeated C-fibre stimulation and the related post-discharges at doses which had minimal effects on the C and A-fibre inputs onto the cells although these were reduced by higher doses of the antagonist. Only the effects on post-discharges and wind-up were reversed by application of glycine. Furthermore the neuronal responses to formalin were also reduced by 7CK at doses which did not influence input. The results show that activation of the glycine site is a requirement for spinal NMDA receptor activation and further emphasize the involvement of this receptor in maintained nociceptive processes
Deletion of annexin 2 light chain p11 in nociceptors causes deficits in somatosensory coding and pain behavior
No full textThe S100 family protein p11 (S100A10, annexin 2 light chain) is involved in the trafficking of the voltage-gated sodium channel Na(V)1.8, TWIK-related acid-sensitive K+ channel (TASK-1), the ligand-gated ion channels acid-sensing ion channel 1a (ASIC1a) and transient receptor potential vanilloid 5/6 (TRPV5/V6), as well as 5-hydroxytryptamine receptor 1B (5-HT1B), a G-protein-coupled receptor. To evaluate the role of p11 in peripheral pain pathways, we generated a loxP-flanked (floxed) p11 mouse and used the Cre-loxP recombinase system to delete p11 exclusively from nociceptive primary sensory neurons in mice. p11-null neurons showed deficits in the expression of NaV1.8, but not of annexin 2. Damage-sensing primary neurons from these animals show a reduced tetrodotoxin-resistant sodium current density, consistent with a loss of membrane-associated NaV1.8. Noxious coding in wide-dynamic-range neurons in the dorsal horn was markedly compromised. Acute pain behavior was attenuated in certain models, but no deficits in inflammatory pain were observed. A significant deficit in neuropathic pain behavior was also apparent in the conditional-null mice. These results confirm an important role for p11 in nociceptor function
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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