Central Hypersensitivity Research Articles

Altered chloride homeostasis in neuropathic pain; functional consequences

Event Abstract Back to Event Altered chloride homeostasis in neuropathic pain; functional consequences Yves De Koninck1* 1 Université Laval Centre hospitalier Robert-Giffard, Centre de recherche , Canada We have previously found a depolarizing shift in Cl- reversal potential in dorsal horn neurons as a potential substrate of disinhibition underlying central hypersensitivity following peripheral nerve injury. This is due to a decrease in expression of the K+-Cl- cotransporter KCC2 in superficial dorsal horn neurons in response to BDNF secretion by activated spinal microglia. Replicating the action of activated microglia and/or inhibition of KCC2 was sufficient to unmask innocuous mechanical input to normally nociceptive specific spinal projection neurons, providing a substrate for tactile allodynia (nociceptive response to a normally innocuous stimulus). To further study the functional impact of altered Cl- homeostasis at the cellular level, we performed computer-based simulations using an electro-diffusion compartmental model. The results reveal that even a small reduction in Cl- gradient compromises inhibitory control of firing rate by reducing both hyperpolarizing inhibition and, indirectly, the efficacy of shunting inhibition. In addition, a low Cl- extrusion capacity causes a rapid collapse in GABAA/glycine-mediated hyperpolarization upon repetitive activity. Small reductions in Clextrusion may be compensated for by increased glycine/GABAA receptor-mediated input, but compensation fails as Cl- accumulates beyond a critical value. Furthermore, compensation by increased glycine/GABAA input introduces instability into the system, rendering it increasingly prone to abrupt switches to paradoxical excitation. In contrast, potentiating Clextrusion appears a more secure means to restore inhibition. The latter strategy also has the advantage of preferentially targeting affected cells because of an inherent non-linearity in the efficacy of KCC2 to alter [Cl-]i: increasing transporter function has minimal impact at low [Cl-]i, but a strong impact at high [Cl-]i. These data illustrate the importance of choosing therapies not only based on disease mechanism, but also on quantitative understanding of that mechanism. Conference: 3rd Mediterranean Conference of Neuroscience , Alexandria, Egypt, 13 Dec - 16 Dec, 2009. Presentation Type: Oral Presentation Topic: Symposium 04 – Dis-inhibition processes in pain sensitization Citation: De Koninck Y (2009). Altered chloride homeostasis in neuropathic pain; functional consequences. Front. Neurosci. Conference Abstract: 3rd Mediterranean Conference of Neuroscience . doi: 10.3389/conf.neuro.01.2009.16.017 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 18 Nov 2009; Published Online: 18 Nov 2009. * Correspondence: Yves De Koninck, Université Laval Centre hospitalier Robert-Giffard, Centre de recherche, Québec, Canada, Yves.Dekoninck@fmed.ulaval.ca Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Yves De Koninck Google Yves De Koninck Google Scholar Yves De Koninck PubMed Yves De Koninck Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Could glial activation be a factor in migraine?

Migraine represents a central neural hypersensitivity. During an attack, migraine sufferers can be hypersensitive to normal levels of sound, light, smell and movement. Sensory processing dysfunction in the brain stem or diencephalic nuclei has been implicated. Most scientific migraine research has focused on neuronal function because of their central role in the processing, integration and transmission of sensory information. However the supporting glia, their receptors and their secreted mediators are now recognised as having an important role in neuronal function regulation. Activated microglia and astrocytes produce and release a variety of neuroexcitatory substances including nitric oxide, excitatory amino acids and proinflammatory cytokines. Spinal glial activation and the subsequent release of proinflammatory mediators initiate and maintain a range of enhanced pain states. The focus on neuronal function has ignored the potential contribution of glial cell activation to neural hypersensitivity and pain. If the central neuronal hypersensitivity associated with migraine represents glial cell activation, drugs that block glial cell activation and the subsequent release of neuroexcitatory substances could have therapeutic potential in both acute migraine treatment and migraine prophylaxis.

New method for quantification and statistical analysis of nociceptive reflex receptive fields in humans

A method for quantifying nociceptive withdrawal reflex receptive fields in human volunteers and patients is described. The reflex receptive field (RRF) for a specific muscle denotes the cutaneous area from which a muscle contraction can be evoked by a nociceptive stimulus. The method is based on random stimulations presented in a blinded sequence to 10 stimulation sites. The sensitivity map is derived by interpolating the reflex responses evoked from the 10 sites. A set of features describing the size and location of the RRF is presented based on statistical analysis of the sensitivity map within every subject. The features include RRF area, volume, peak location and center of gravity. The method was applied to 30 healthy volunteers. Electrical stimuli were applied to the sole of the foot evoking reflexes in the ankle flexor tibialis anterior. The RRF area covered a fraction of 0.57 ± 0.06 (S.E.M.) of the foot and was located on the medial, distal part of the sole of the foot. An intramuscular injection into flexor digitorum brevis of capsaicin was performed in one spinal cord injured subject to attempt modulation of the reflex receptive field. The RRF area, RRF volume and location of the peak reflex response appear to be the most sensitive measures for detecting modulation of spinal nociceptive processing. This new method has important potential applications for exploring aspects of central plasticity in volunteers and patients. It may be utilized as a new diagnostic tool for central hypersensitivity and quantification of therapeutic interventions.

Magical ideation and hyperacusis

The subjective experience conferred by auditory perception has rarely been addressed outside of the studies of auditory hallucinations. The aim of this study is to describe the phenomenology of auditory experiences in individuals who endorse magical beliefs, but do not report hallucinations. We examined the relationship between subjective auditory sensitivity and a ‘psychotic-like’ thinking style. Hyperacusis questionnaire scores were compared between 25 high scoring participants on Chapman's magical ideation (MI) scale, 25 high scoring participants on Chapman's physical anhedonia scale and 25 control participants, pre-selected from a large student pool ( n = 1289). The participants who obtained high scores on the MI scale rated their auditory sensitivity higher than the two other groups. Our results indicate that, in healthy subjects, subjective auditory sensitivity is associated with MI without the mediation by anxiety commonly observed in pathological cases. We propose that hyperacusis associated to high scores of MI may be a predispositional factor to deviant auditory experiences. The relative uncoupling of perception from auditory sensory input may result in a central hypersensitivity, which could play a role in triggering off the experience of auditory hallucinations.

Bradykinin Enhances AMPA and NMDA Receptor Activity in Spinal Cord Dorsal Horn Neurons by Activating Multiple Kinases to Produce Pain Hypersensitivity

Bradykinin potentiates synaptic glutamate release and action in the spinal cord via presynaptic and postsynaptic B(2) receptors, contributing thereby to activity-dependent central sensitization and pain hypersensitivity (Wang et al., 2005). We have now examined the signaling pathways that are responsible for the postsynaptic modulatory actions of bradykinin on glutamatergic action and transmission in superficial dorsal horn neurons. B(2) receptors are coexpressed in dorsal horn neurons with protein kinase A (PKA) and the delta isoform of protein kinase C (PKC), and we find that the augmentation by bradykinin of AMPA and NMDA receptor-mediated currents in lamina II neurons requires coactivation of both PKC and PKA. The activation of PKA is downstream of COX1 (cyclooxygenase-1). Extracellular signal-regulated kinase (ERK) activation is involved after the PKC and PKA coactivation, and intrathecal administration of bradykinin induces a thermal hyperalgesia in vivo, which is reduced by inhibition of ERK, PKA, and PKC. We conclude that bradykinin, by activating multiple kinases in dorsal horn neurons, potentiates glutamatergic synaptic transmission to produce pain hypersensitivity.

Endogenous kappa-opioid receptor systems inhibit hyperalgesia associated with localized peripheral inflammation

Peripheral inflammation evokes functional and biochemical changes in the periphery and spinal cord which result in central sensitization and hypersensitivity. Inhibitory control systems from the rostral ventromedial medulla (RVM) are also activated. The present study investigates whether endogenous kappa-opioid receptor (KOPr) systems contribute to these neuroadaptations. Inflammation was induced by intraplantar injection of complete Freund’s adjuvant (CFA) into one hindpaw. Mechanical and thermal thresholds were determined using the Von Frey and radiant heat tests, respectively. KOPr gene deletion in mice or systemic administration of the long-acting KOPr antagonist, norbinaltorphimine (norBNI) significantly exacerbated mechanical and thermal hypersensitivity of the ipsilateral, inflamed paw. Thermal and mechanical thresholds of the non-inflamed, contralateral hindpaw were unaffected by CFA treatment. However, gene deletion as well as norBNI treatment resulted in mechanical, but not thermal hypersensitivity of the non-inflamed paw. Similar results were obtained when norBNI was administered intrathecally or into the RVM in rats. These data demonstrate a previously unrecognized role of endogenous KOPr systems in inhibiting hyperalgesia during inflammation. Furthermore, they demonstrate that decreased KOPr activity in either the spinal cord or RVM not only enhances mechanical and thermal hyperalgesia of the inflamed limb but also leads to an unmasking of mechanical hyperalgesia at a site remote from inflammation. The differential effects of KOPr antagonism on mechanical versus thermal thresholds for the non-inflamed paw support the notion that distinct neuroanatomical or neurochemical mechanisms modulate the processing of thermal versus mechanical stimuli.

Psychologic Factors Are Related to Some Sensory Pain Thresholds but Not Nociceptive Flexion Reflex Threshold in Chronic Whiplash

Sensory hypersensitivity, central hyperexcitability [lowered nociceptive flexion reflex (NFR) thresholds], and psychologic distress are features of chronic whiplash. However, relationships between these substrates are not clear. This study tested the hypothesis that psychologic distress and catastrophization are correlated with sensory hypersensitivity and NFR responses in chronic whiplash. Pressure and thermal pain thresholds (mean values across 3 body sites), NFR threshold, and pain at threshold Visual Analog Scale were measured in 30 participants with chronic whiplash and 30 asymptomatic controls. Pain and disability levels Neck Disability Index, psychologic distress (GHQ-28), and catastrophization (PCS) were also measured in the whiplash group. Whiplash injured participants demonstrated lowered pain thresholds to pressure and cold (P<0.05); lowered NFR thresholds (P=0.003), and demonstrated above threshold levels of psychologic distress (GHQ-28) and levels of catastrophization comparable with other musculoskeletal conditions. There were no group differences for heat pain thresholds or pain at NFR threshold. In the whiplash group, PCS scores correlated moderately with cold pain threshold (r=0.51, P=0.01). In contrast, there were no significant correlations between GHQ-28 scores and pain threshold measures or between psychologic factors and NFR responses in whiplash participants. There were no significant correlations between psychologic factors and pain thresholds or NFR responses in controls. We have demonstrated that psychologic factors have some association with sensory hypersensitivity (cold pain threshold measures) in chronic whiplash but do not seem to influence spinal cord excitability. This suggests that psychologic disorders are important, but not the only, determinants of central hypersensitivity in whiplash patients.

Oral nabilone capsules in the treatment of chemotherapy-induced nausea and vomiting and pain

Background: Nabilone has been approved to treat chemotherapy-induced nausea and vomiting. Recent studies have explored cannabinoids in pain management. Objectives: To review the evidence for the use of cannabinoids in general and nabilone in particular; i) in managing chemotherapy-induced nausea and vomiting; and ii) in treating pain. Method: A systematic review of published English literature used the terms: cancer, cannabinoid, nabilone, nausea, pain, tetrahydrocannabinol and vomiting as search terms. Reviews, meta-analyses and treatment trials were reviewed. Results/conclusions: Nabilone is superior to placebo, domperidone and prochlorperazine but not metoclopramide or chlorpromazine. Cannabinoids do not add to benefits of 5-HT3 receptor antagonists. Side effects are greater for nabilone than for prochlorperazine, in most studies patients prefered nabilone over prochlorperazine. Nabilone is ineffective in acute pain but benefits in neuropathic pain and central hypersensitization. Recent guidelines place nabilone as a second to fourth line drug for neuropathic pain.

Thermal and Visceral Hypersensitivity in Irritable Bowel Syndrome Patients With and Without Fibromyalgia

Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by both visceral and somatic hyperalgesia, producing a similar effect seen with the central hypersensitivity mechanism in fibromyalgia (FM). The aim of the current study was to compare magnitudes of visceral and thermal hypersensitivity in IBS patients and FM patients with IBS (FM+IBS) compared with healthy controls. Female patients with IBS (n=12), FM+IBS (n=12), and control participants (n=13) rated pain intensity to hot water immersion (45 and 47 degrees C) of the hand/foot and to phasic distension of the rectum (35, 55 mm Hg) on a Mechanical Visual Analog Scale. The data were analyzed with 3 separate 1-way analyses of variance with post hoc Tukey tests. For both thermal and visceral stimuli, the control group had lower pain ratings than either the IBS or FM+IBS groups (P<0.001). IBS patients rated rectal distension as more painful than the FM+IBS group (P=0.005). During hot water immersion of the foot, the FM+IBS group had higher pain ratings than the IBS group (P<0.001). During hand immersion, FM+IBS and IBS patients did not significantly differ in their pain intensity ratings (P=0.4). FM+IBS patients show greater thermal hypersensitivity compared with IBS patients. However, IBS patients exhibit higher pain ratings to rectal distension compared with FM+IBS patients. This data suggests that regions of primary and secondary hyperalgesia are dependent on the primary pain complaint.

Quantitative Analysis of Respiratory Chemoreflex System in Rats with Chronic Heart Failure ‐Analytical Approach to Underlying Mechanism of Ventilatory Abnormality‐

Background: To understand the pathophysiologic basis of exercise hyperpnea in chronic heart failure (CHF), based on the control theory, we have developed an experimental method quantitatively characterizing ventilatory regulation system in rats. An equilibrium diagram illustrates the characteristics of two subsytems, i.e., the controller (arterial CO2 tension [PaCO2] → minute ventilation [VE] relation) and plant (VE→PaCO2 relation). In this study, we compared these between normal and CHF rats at rest. Method: In anesthetized 6 postinfarction CHF rats and 6 normal rats, we induced hypercapnia by changing inspiratory CO2 fraction and measured the steady-state PaCO2→VE relation. We altered VE by varying the level of artificial ventilation and measured the VE→PaCO2 relation. Results: Controller gain S was significantly lager in CHF rats, confirming clinical observation. The VE at rest (operating point) in CHF was 24 % larger; central hypersensitivity, however, contributed little (6 %) to this increase. Conclusion: Central hypersensitivity alone would not explain hyperpnea at rest in CHF rats. Considering the right and upward shift of VE→PaCO2 relation, central hypersensitivity contributes more to hyperpnea during exercise. The potential difference between normal and CHF rats in exercise-induced changes in controller and plant should be examined to fully understand the mechanism of exercise hyperpnea and to develop a method to attenuate this.

Modulation of central leptin sensitivity and energy balance in a rat model of diet‐induced obesity

The aim of this study was to further explore the time-dependent changes in leptin sensitivity using a rat model of dietary fat-induced obesity and to investigate the potential mechanisms governing these changes. We used male, adult Sprague-Dawley rats that were fed either a standard laboratory chow diet (3% fat) or a high-saturated fat (HF) diet (60% fat) for 2 or 5 weeks. Energy balance (body weight, energy intake and energy expenditure); sensitivity to central leptin and central alpha-melanin stimulating hormone (alpha-MSH) administration and expression levels of hypothalamic ObRb, signal transducers and activators of transcription factor (STAT)-3 phosphorylation, suppressor of cytokine signalling-3 (SOCS-3), proopiomelanocortin (POMC) processing hormones (prohormone convertase-1 and prohormone convertase-2) and neuropeptide Y (NPY) were measured. After 2 weeks of feeding HF diet, there was an increase in total energy intake (TEI) but a reduction in food intake as measured by the mass of food ingested. Body weight at this time was not significantly different between the two diet groups; however, white adipose tissue (WAT) weight was significantly greater in the HF-fed rats than in the chow-fed rats. In addition, spontaneous physical activity levels were increased, but no changes were observed in resting energy expenditure. Furthermore, chow-fed lean rats responded to central leptin administration by reducing the energy intake by approximately 67 kJ compared with saline treatment (p < 0.05), while the HF-fed diet-induced obese (DIO) rats responded by reducing their energy intake by approximately 197 kJ compared with saline treatment (p < 0.05). After 5 weeks of feeding HF diet, TEI remained significantly higher, body weight was significantly increased by 5% in the HF-fed rats and WAT weight was significantly heavier in HF-fed rats than in the chow-fed lean rats. After leptin treatment, the chow-fed lean rats reduced their energy intake by approximately 97 kJ (p < 0.05); yet, leptin had no significant effect in the HF-fed DIO rats. ObRb protein expression, STAT-3 phosphorylation levels, content and messenger RNA (mRNA) expression of NPY, SOCS-3 mRNA and protein expression and energy intake response to central alpha-MSH administration were not altered after HF diet feeding. These results suggest that early in the course of HF diet-induced weight gain, there was a period of central leptin hypersensitivity, and as the obesity progresses, central leptin insensitivity develops. This insensitivity does not appear to be explained by a downregulation of ObRb protein levels, reduced leptin signalling, an increase in either SOCS-3 or NPY expression or reduced function of the melanocortin system. The effect of an HF diet on other actions of leptin such as its effect on the endocannabinoid system should be investigated.

ApoE allelic variability influences pupil response to cholinergic challenge and cognitive impairment

Exaggerated pupil response to dilute tropicamide has been suggested as an early biological marker for Alzheimer's disease. The current study links apolipoprotein E (ApoE) allelic variability to the magnitude of pupil response in a sample of community-dwelling elderly without a diagnosis of Alzheimer's disease or dementia. Possession of an epsilon 4 allele influences both the likelihood of exhibiting an exaggerated pupil response above a predetermined cut-off (13% above baseline diameter) and the absolute overall magnitude of the response. Allelic variability was also shown to correlate with cognitive impairments in memory and attention. The data in this study further elucidate the nature of the biological bond between an exaggerated pupil response and the pathology of Alzheimer's disease. ApoE allelic variability is probably linked to pupil response through its influence on tau hyperphosphorylation. The early Alzheimer's pathology seen in the Edinger-Westphal area of cranial nerve III, a major centre for pupil control, is primarily tau-based with significant cell loss in this nucleus leading to central denervation hypersensitivity even in elderly who are clinically silent but who have early pathology.

Sciatic Chronic Constriction Injury Produces Cell-Type-Specific Changes in the Electrophysiological Properties of Rat Substantia Gelatinosa Neurons

Peripheral nerve injury increases spontaneous action potential discharge in spinal dorsal horn neurons and augments their response to peripheral stimulation. This "central hypersensitivity, " which relates to the onset and persistence of neuropathic pain, reflects spontaneous activity in primary afferent fibers as well as long-term changes in the intrinsic properties of the dorsal horn (centralization). To isolate and investigate cellular mechanisms underlying "centralization," sciatic nerves of 20-day-old rats were subjected to 13-25 days of chronic constriction injury (CCI; Mosconi-Kruger polyethylene cuff model). Spinal cord slices were then acutely prepared from sham-operated or CCI animals, and whole cell recording was used to compare the properties of five types of substantia gelatinosa neuron. These were defined as tonic, irregular, phasic, transient, or delay according to their discharge pattern in response to depolarizing current. CCI did not affect resting membrane potential, rheobase, or input resistance in any neuron type but increased the amplitude and frequency of spontaneous and miniature excitatory postsynaptic currents (EPSCs) in delay, transient, and irregular cells. These changes involved alterations in the action potential-independent neurotransmitter release machinery and possible increases in the postsynaptic effectiveness of glutamate. By contrast, in tonic cells, CCI reduced the amplitude and frequency of spontaneous and miniature EPSCs. Such changes may relate to the putative role of tonic cells as inhibitory GABAergic interneurons, whereas increased synaptic drive to delay cells may relate to their putative role as the excitatory output neurons of the substantia gelatinosa. Complementary changes in synaptic excitation of inhibitory and excitatory neurons may thus contribute to pain centralization.

Central hypersensitivity in whiplash: implications for physiotherapy assessment and management

It is emerging that whiplash-associated disorder (WAD) is a complex condition characterised by a variety of physical and psychological features. Generalised sensory hypersensitivity is one of these features and its presence reflects augmented central pain processing mechanisms. Whilst most studies have investigated these processes in chronic WAD, it is becoming clear that in some of the whiplash injured, sensory disturbances are present from soon after injury, and are associated with both poor recovery and recalcitrance to multimodal physiotherapy interventions. Evidence for sensory hypersensitivity in WAD and possible underlying mechanisms of these phenomena are reviewed. Physiotherapists play an important role in the evaluation and management of whiplash injury. It is important that sensory disturbances be identified early in the clinical assessment of the whiplash injured patient and that ensuing management strategies address these changes, if the aim of treatment is to prevent the transition to chronicity.

Comparison of Visceral and Somatic Pain Sensitivity in Irritable Bowel Syndrome Patients with and without Fibromyalgia

Purpose: Recent studies have shown that patients with irritable bowel syndrome (IBS) exhibit both visceral and somatic hyperalgesia. This is similar in effect to the central hypersensitivity mechanism seen in patients with Fibromyalgia (FM). The aim of the present study was to compare the magnitude of visceral and thermal hypersensitivity in IBS patients and Fibromyalgia patients with IBS (FMS + IBS) compared to age/sex matched healthy controls. Methods: Fifteen patients (12 F, 3 M) with IBS, ten patients (10 F) with FMS, and seventeen control subjects (13 F, 4 M), rated pain intensity and unpleasantness to hot water immersion (45 and 47°C) of the hand/foot and phasic distension of the rectum (35, 55 mmHg) on a 0–10 M-VAS scale. The data was analyzed with 3 separate one-way ANOVA's with Post-hoc Tukey tests. Results: When comparing both thermal and visceral stimuli, the control group had lower pain ratings than either the IBS or FMS + IBS groups (p < 0.001). IBS patients rated rectal distension as more painful than the FMS +IBS group (p = 0.004). During hot water immersion of the foot, the FMS + IBS group had higher pain ratings than the IBS group (P = 0.027). During hand immersion, FMS + IBS and IBS patients did not significantly differ in their pain intensity ratings (P = 0.15). Both patient groups had higher scores than controls to somatic focus, state anxiety, and depression. No significant differences were found between the IBS and FMS + IBS groups on any psychological measures. Conclusions: FMS + IBS patients show greater thermal hypersensitivity compared to IBS patients. However, IBS patients exhibit higher pain ratings to rectal distension compared to FMS + IBS patients. These data suggest that regions of primary and secondary hyperalgesia are to some extent dependent on the primary pain complaint.

Pain Thresholds in Daily Transformed Migraine Versus Episodic Migraine Headache Patients

The objective of this study was to test whether pain thresholds of patients with episodic migraine (EM) are significantly different from transformed migraine (TM) patients as measured by Quantitative Sensory Testing (QST) and Semmes-Weinstein Monofilaments (SW). Although there are many theories, none have undeniably proven why many TM patients are refractory to triptans and other gold standard medications. The hypothesis was that baseline pain thresholds of TM patients are lower than EM patients. Episodic (n = 40) and Transformed (n = 41) migraineurs with and without aura were examined with QST and SW over eight locations (bilateral ophthalmic, maxillary, C4/posterior neck, and forearm). All patients completed two visits, baseline and severe migraine. TM patients have lower pain thresholds, than EM patients, as measured on QST and SW testing. A total of 81 out of 129 patients completed both parts of the study at baseline and severe migraine. There were significant differences (P < .05) between EM and TM groups at baseline on maxillary, neck (EM = 45.91 degrees C and TM = 42.94 degrees C), and arm. TM patients, clinically known to report skin hypersensitivity during migraine, were found to have lower pain thresholds than EM patients, both with severe migraine, and at baseline, measured by QST and SW mechanical testing. As with Burstein's work in EM patients with lowered pain thresholds during their acute migraine, central sensitization may be the explanation for non-responsiveness to triptans in a high proportion of TM patients. The difference in pain threshold at the neck location was such a strikingly frequent difference between EM and TM patients, that this indicates the need for future research to clarify the directional relationship and the relative importance of muscular versus peripheral versus central hypersensitivity in the determination of allodynia.

Adverse Effects Associated With Antiretroviral Therapy and Potential Management Strategies

A variety of adverse drug reactions (ADRs) affecting many organ systems may be observed with antiretroviral therapy (ARV), and they can be differentiated into short- and long- term effects, class effects, or individual drug effects. Commonly seen ADRs include dermatological reactions, associated with nonnucleoside reverse transcriptase inhibitors (NNRTIs) and some protease inhibitors (PIs), and gastrointestinal problems, a major side effect of PIs and of some nucleoside reverse transcriptase inhibitors (NRTIs). Metabolic complications are frequently reported in HIV-infected patients on ARV and often coexist. Lipodystrophy, hyperinsulinemia/hyperglycemia, and bone disorders (osteoporosis, osteonecrosis) are mainly associated with PIs, while lactic acidemia/acidosis are primarily a problem of NRTIs. Hyperlipidemia may be caused by almost all PIs, few NRTIs, and NNRTIs. All antiretroviral drug classes may cause both asymptomatic and symptomatic hepatotoxicity, although nevirapine is the agent most implicated in hepatic events. More drug-specific ADRs include nephrotoxicity (indinavir and tenofovir), central nervous system problems (efavirenz), hematological disturbances (zidovudine), and hypersensitivity reactions (abacavir). Anticipation of ADRs may influence a patient’s decision to delay ARV or to choose specific and potentially less active agents. Occurrence of ADRs may significantly impact a patient’s quality of life and drug adherence. Pharmacists counseling HIV-infected patients should be aware of common ADRs with ARV and potential management strategies.

Flexor carpi radialis motoneuron pool in subjects with chronic carpal tunnel syndrome are more excitable than matched control subjects

We compared excitability of the flexor carpi radialis (FCR) motoneuron pool in subjects with and without carpal tunnel syndrome (CTS). The study involved 11 subjects with chronic idiopathic CTS and 11 asymptomatic subjects as controls. The H-reflex and M-response of FCR muscle were obtained by stimulating the median nerve in the cubital fossa in the presence of an isometric background contraction using surface stimulating and recording electrodes. There was a significantly higher H-reflex latency and amplitude and H max / M max in CTS subjects ( P < 0.0 5 ). Latency and amplitude of the M-response remained unaffected in CTS group. The results support the hypothesis that central hypersensitivity does occur in chronic CTS. Therefore even in the presence of pathology in peripheral structures central mechanisms should be considered by clinicians.

La femme endométriosique est-elle différente ?

The objective of this short review is to identify the particularities of women with endometriosis, especially those complaining of pain and with the most severe lesions. Genetic aberrations play, with a high probability, a major role in the development of this disease, its severity, its tendency to recur and also in its capacity to degenerate. The abnormalities of the endometrium, with exacerbated biological activities, are an example. The woman with endometriosis seems more sensitive to pain through various mechanisms, such as central hypersensitivity and decrease threshold to somatoceptive pain and several associated psychological disorders. Endometriosis is often associated with other painful conditions such as irritable bowel syndrome, interstitial cystitis and fibromyalgia. Finally, also appears also to have a higher risk to develop non Hodgkin's lymphoma or ovarian cancer. These particularities, some of them being still speculative or controversial, should be known in routine practise, in order to offer a better multidisciplinary management, not only for short term, but also long term issues.

Serotonin Mechanisms in Pain and Functional Syndromes

A young woman presented with multiple central hypersensitivity disorders, including fibromyalgia, headache, pelvic pain and several smooth muscle spasm disorders, including irritable bowel syndrome, irritable bladder and Raynaud's phenomenon. She also had significant fatigue and sleep problems. Her case illustrates the importance and surprising frequency of atypical bipolar mood disorders in people with multiple central hypersensitivity pain disorders, especially with depression and anxiety resistant to antidepressant treatment. Considering neurological mechanisms common to her overlapping disorders was very helpful in guiding treatment choices. This experience illustrates the value of serotonin receptor type 2 (5HT2) inhibition with atypical neuroleptics, of neural cation channel and glutamate inhibition with anticonvulsants, and the potential usefulness of antidepressants after establishing 5HT2 control to enhance downward inhibitory tracts. Medications with combined usefulness for both bipolar mood and pain disorders were highly effective for her multiple hypersensitivity problems.