The formalin test does not probe inflammatory pain but excitotoxicity in rodent skin.

The most widely used formalin test to screen antinociceptive drug candidates is still apostrophized as targeting inflammatory pain, in spite of strong opposing evidence published. In our rat skin-nerve preparation ex vivo, recording from all classes of sensory single-fibers (n = 32), 30 units were transiently excited by formaldehyde concentrations 1-100 mM applied to receptive fields (RFs) for 3 min, C and Aδ-fibers being more sensitive (1-30 mM) than Aß-fibers. From 30 mM on, ~1% of the concentration usually injected in vivo, all RFs were defunctionalized and conduction in an isolated sciatic nerve preparation was irreversibly blocked. Thus, formaldehyde, generated a state of 'anesthesia dolorosa' in the RFs in so far as after a quiescent interphase all fibers with unmyelinated terminals developed a second phase of vigorous discharge activity which correlated well in time course and magnitude with published pain-related behaviors. Sural nerve filament recordings in vivo confirmed that higher formalin concentrations (> 42 mM) have to be injected to the skin to induce this second phase of discharge. Patch-clamp and calcium-imaging confirmed TRPA1 as the primary transducer of formaldehyde (10 mM) effects on mouse sensory neurons. However, stimulated CGRP release from isolated skin of TRPA1+/+ and TRPA1-/- mice showed a convergence of the saturating concentration-response curves at 100 mM formaldehyde, which did not occur with nerve and trachea preparations. Finally, skin-nerve recordings from C and Aδ-fibers of TRPA1-/- mice revealed a massive reduction in formaldehyde (30 mM)-evoked discharge. However, the remaining activity was still biphasic, thus confirming additional unspecific excitotoxic actions of the fixative that diffuses along still excitable axons as previously published. The multiplicity of formaldehyde's actions requires extensive discussion and literature review, leading to a fundamental reevaluation of the formalin test.

Sleep Disturbances and Osteoarthritis.

Sleep disturbances are particularly troublesome in patients with painful rheumatic disease. This article reviews the literature specifically published on sleep disturbances in osteoarthritis, a prevalent pathology and leading cause of disability. Several aspects of the relationship between sleep and osteoarthritis are discussed, including epidemiology, pathophysiological hypotheses, and treatment outcomes. Sleep is of central importance in the well-being of patients and should systematically be assessed in patients with osteoarthritis. When needed, a specific treatment of sleep disorders should be associated with an optimal management of pain to achieve synergistic improvements in quality of life. More large-scale studies are needed to identify predictive factors of sleep impairment in osteoarthritis.

Phase advance of circadian rhythms in Smith-Magenis syndrome: a case study in an adult man.

Melatonin secretion is usually increased during the daytime and decreased at night in Smith-Magenis syndrome (SMS) and consequently is not a pertinent marker of the circadian phase of the clock in these cases. No data on temperature rhythm is available in SMS, another reliable marker of circadian clock activity. For this reason, we assessed the 24h profiles of core temperature, sleep-wake cycle, hormones (plasma cortisol and melatonin) and plasma and urine 6sulfatoxy-melatonin, the main hepatic melatonin metabolism in a 31-year-old man diagnosed with a SMS. All circadian rhythms, especially temperature rhythm showed a phase-advance, associated with reverse melatonin secretion. Plasma and urine 6sulfatoxy-melatonin profiles showed normal melatonin catabolism and confirmed the reversed melatonin secretion. Taking in consideration the reverse melatonin secretion and the phase-advanced temperature rhythm, which is driven by the suprachiasmatic nucleus, we hypothesize that the central clock is more sensitive to afternoon than to morning melatonin. This different responsiveness to melatonin according to the time of the day (i.e. chronaesthesia) corroborates the phase response curve of melatonin secretion to exogenous melatonin.

Chronic pseudo-angina left precordial chest pain caused by a thoracic meningioma.

Left precordial chest pain (LPCP) evokes above all angina. Eliminating a cardiac origin is then always the first priority. When cardiac causes are eliminated, non-cardiac causes are sought in order to avoid leaving patients with undiagnosed or undifferentiated chest pain. There is a myriad of non-cardiac causes ranging from heartburn, panic attacks, pleurisy, pulmonary embolism, pneumothorax, Tietze syndrome, bruises and fractures of the ribs, to spine meningioma, neuroma, herniated disk and impairment of the nerve roots. Although clinical presentation and characteristics of the pain are usually helpful in diagnosing the cause, conducting magnetic resonance imaging of the spine may be of a high utility in some situations. Here we report a case of chronic angina-like LPCP, caused by a thoracic meningioma. .

Persistence of fertility despite semen alterations in a pinealectomised patient treated with melatonin.

OBJECTIVES: Little is known about the effect of chronic melatonin treatment on human reproductive function. We report here on the effect of 10 months treatment with a controlled-release melatonin preparation (Circadin®, 2 mg) on spermatogenesis and gonadotropic hormone status in a pinealectomised patient whose melatonin secretion was abolished. METHODS: Semen analysis, hormone (Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), inhibin B, prolactin, testosterone and estradiol) and Sex Hormone-Binding Globulin (SHB G) concentrations were determined before and at the end of 4 and 10 months of, treatment. RESULTS: At the end of treatment, testosterone, sex hormone-binding globulin, prolactin and inhibin B levels did not display significant variation with time, whereas FSH and LH levels showed a tendency to a decrease, but remained in the normal range. Sperm concentration and total spermatozoa count dropped below the lower limit of the reference range during melatonin treatment, whereas motility and normal form percentages remained in the normal range. Fertility was preserved, since the patient's wife became pregnant during month 10 of melatonin treatment and gave birth to a healthy female baby. CONCLUSIONS: this isolated clinical observation shows that more investigations in large patient series are needed to document possible side-effects of melatonin administration on male reproductive function. One should therefore be cautious about melatonin prescription for circadian rhythm sleep disorders in young males.

An inverse agonist of the histamine H(3) receptor improves wakefulness in narcolepsy: studies in orexin-/- mice and patients.

Narcolepsy is characterized by excessive daytime sleepiness (EDS), cataplexy, direct onsets of rapid eye movement (REM) sleep from wakefulness (DREMs) and deficiency of orexins, neuropeptides that promote wakefulness largely via activation of histamine (HA) pathways. The hypothesis that the orexin defect can be circumvented by enhancing HA release was explored in narcoleptic mice and patients using tiprolisant, an inverse H(3)-receptor agonist. In narcoleptic orexin(-/-) mice, tiprolisant enhanced HA and noradrenaline neuronal activity, promoted wakefulness and decreased abnormal DREMs, all effects being amplified by co-administration of modafinil, a currently-prescribed wake-promoting drug. In a pilot single-blind trial on 22 patients receiving a placebo followed by tiprolisant, both for 1 week, the Epworth Sleepiness Scale (ESS) score was reduced from a baseline value of 17.6 by 1.0 with the placebo (p>0.05) and 5.9 with tiprolisant (p<0.001). Excessive daytime sleep, unaffected under placebo, was nearly suppressed on the last days of tiprolisant dosing. H(3)-receptor inverse agonists could constitute a novel effective treatment of EDS, particularly when associated with modafinil.

Increased REM sleep associated with melatonin deficiency after pinealectomy: a case study.

The objectives of the investigation were to assess hypersomnia, which progressively appeared in a young patient after a pinealectomy, chemotherapy, and radiotherapy for a typical germinoma, as well as the potential benefit of melatonin administration in the absence of its endogenous secretion. 24 h ambulatory polysomnography and the Multiple Sleep Latency Test (MSLT) were performed; in addition, daily plasma melatonin, cortisol, growth hormone, prolactin, and rectal temperature profiles were determined before and during melatonin treatment (one 2 mg capsule given nightly at 21:00 h for 4 weeks). MSLT showed abnormal sleep latency and two REM sleep onsets. Nighttime total sleep duration was lengthened, mainly as a consequence of an increased REM sleep duration. These parameters were slightly modified by melatonin replacement. Plasma melatonin levels, which were constantly nil in the basal condition, were increased to supraphysiological values with melatonin treatment. The plasma cortisol profile showed nycthemeral variation within the normal range, and the growth hormone profile showed supplementary diurnal peaks. Melatonin treatment did not modify the secretion of either hormone. The plasma prolactin profile did not display a physiological nocturnal increase in the basal condition; however, it did during melatonin treatment, with the rise coinciding with the nocturnal peak of melatonin concentration. A 24 h temperature rhythm of normal amplitude was persistent, though the mean level was decreased and the rhythm was dampened during melatonin treatment. The role of radiotherapy on the studied parameters cannot be excluded; the findings of this case study suggest that the observed hypersomnia is not the result of melatonin deficiency alone. Overall, melatonin treatment was well tolerated, but the benefit on the sleep abnormality, especially on daytime REM sleep, was minor, requiring the re-introduction of modafinil treatment.

The effect of carrageenan-induced inflammation on the sensitivity of unmyelinated skin nociceptors in the rat.

Carrageenan was subcutaneously injected in the area innervated by the saphenous nerve. Part of the mechano-heat sensitive C-fiber receptors (CHM) located inside or at the border of the inflamed area showed an enhanced responsiveness to heat stimulation (sensitization). Those CMH units exhibited spontaneous activity; their mechanical thresholds (von Frey) were higher than those of not spontaneously active fibers. None of the units located outside of the inflamed area displayed sensitization. The data reveal that only part of the CMH units in a uniformly inflamed skin area shows signs of sensitization. Our results are compared to those obtained in other inflammatory processes. The relation to inflammatory pain and to hyperalgesia and the contribution of endogenous substances to sensitization of CMH units are discussed.