Antipruritic effects of transient heat stimulation on histaminergic and nonhistaminergic itch.

BACKGROUND: Chronic itch is notoriously difficult to treat. Counterstimuli are able to inhibit itch, but this principle is difficult to apply in clinical practice, and the mechanisms behind counterstimulation-induced itch suppression in humans are unclear. OBJECTIVES: Firstly, to analyse the stimulus-response effects of transient heat stimuli on histaminergic and nonhistaminergic itch, and secondly, to investigate whether the antipruritic effect depends on homotopic (peripheral mediation) or heterotopic (central mediation) counterstimulation relative to the itch provocation site. METHODS: Eighteen healthy volunteers participated (eight female, mean age 25·7 ± 0·8 years). Itch was evoked on premarked areas of the volar forearms, by either histamine (1% solution) or cowhage (35-40 spicules). In addition to the itch provocations (experiment 1), 5-s homotopic heat stimuli at 32, 40, 45 or 50 °C were applied. In experiment 2, heat stimuli were applied either homotopically, intrasegmentally (next to the provocation site) or extrasegmentally (dorsal forearm). Itch intensity was evaluated throughout the procedures using a digital visual analogue scale. RESULTS: Homotopic counterstimuli inhibited histaminergic itch by 41·3% at 45 °C (P < 0·01) and by 76·7% at 50 °C (P < 0·001). Cowhage-induced itch was less prone to counterstimulation and was significantly diminished only at 50 °C, by 43·6% (P = 0·009). Counterstimulations applied heterotopically were not able to inhibit itch significantly. CONCLUSIONS: Itch pathway-specific effects of counterstimuli were observed between homo- and heterotopic stimulation. Histaminergic itch was robustly inhibited by short-term homotopic noxious heat stimuli for up to 10 min. Nonhistaminergic itch was only weakly inhibited. The inhibitory effects exerted by the short-term heat stimuli only occurred following homotopic counterstimulation.

Nonhistaminergic and mechanical itch sensitization in atopic dermatitis.

Chronic or episodic severe itch is recurrent in atopic dermatitis (AD). Nonhistaminergic itch pathways are suggested to dominate in AD itch, contributing to an "itch-scratch-itch cycle" that prolongs and worsens itch, pain, and skin lesions. We hypothesized that nonhistaminergic neuronal sensitization contributes to itch in AD. Hence, we compared sensitivity with thermal, mechanical, and chemical pruritic stimuli in patients with AD and controls. The study comprised 25 patients with AD with chronic itch and 25 healthy controls. Questionnaires on itch characteristics were administered, and sensory tests were conducted intralesionally, extralesionally, and in homologous areas of controls. Thermal and mechanical quantitative sensory testing (QST) as well as histamine and cowhage provocations were performed. Subsequently, hyperknesis and vasomotor reactivity were assessed. Average itch and associated pain among patients with AD were 60.7 ± 4.3 and 39.7 ± 5.2 (VAS0-100), respectively. Patients experienced significantly higher itch from cowhage both intralesionally and extralesionally compared with controls, whereas histamine-evoked itch intensity was not significantly different between groups. No group differences were found for thermal quantitative sensory testings or pain evoked by itch provocations. Patients had decreased mechanical detection thresholds intralesionally and increased mechanical pain sensitivity intralesionally and extralesionally. Lastly, patients exhibited intralesional and extralesional hyperknesis before chemical itch provocations and augmented hyperknesis after itch provocations. Increased itch in response to cowhage (but not histamine) suggests nonhistaminergic pathway-specific itch sensitization in AD, whereas increased susceptibility to mechanically evoked itch and pain, particularly intralesionally suggests sensitization of mechanosensitive circuitry not normally associated with itch. Drugs targeting the nonhistaminergic (PAR2/TRPA1) itch pathway and itch sensitization are promising for treating AD itch.

Histaminergic and non-histaminergic elicited itch is attenuated in capsaicin-evoked areas of allodynia and hyperalgesia: A healthy volunteer study.

BACKGROUND: Chronic pain patients with sensitization may exhibit decreased sensitivity to normally pruritogenic sensory stimuli and moreover occasionally perceive these as painful. This study explored the relationship between itch and pain, by evaluating histaminergic and non-histaminergic itch evoked in capsaicin-induced allodynic and hyperalgesic areas. METHODS: In 28 healthy volunteers, capsaicin (100 µg/0.1 mL) was injected intradermally in the volar forearm to establish secondary dysesthesias. After the capsaicin-induced pain subsided, the areas of allodynia and hyperalgesia were mapped and itch was provoked inside these areas by histamine (10 mg/mL) and cowhage (25-40 spicules). The evoked itch and pain were recorded on a visual analogue scale (VAS 0-10 cm). Contralateral injection of 0.1 mL isotonic saline served as a control. RESULTS: Histaminergic and non-histaminergic evoked itch were significantly decreased when provoked in allodynic skin (p < 0.05). The area-under-the-curve of the evoked itch was reduced -43% from 18.0 ± 2.6 cm10 min in normal skin to 10.3 ± 1.8 cm10 min in allodynic skin (p < 0.01) for cowhage and -56% from 20.0 ± 3.5 cm10 min in normal skin to 8.8 ± 2.3 cm10 min allodynic skin (p < 0.001) for histamine. The pain responses to the pruritogens were not significantly altered between the areas of allodynia and normal skin (p > 0.1). An additional experiment showed that pinprick hyperalgesia in the absence of allodynia was sufficient to evoke the observed reduced sensitivity to itch stimuli. CONCLUSIONS: Cutaneous sensitization (secondary allodynia and hyperalgesia) reduced itch responses regardless of the type of itch model applied and without attenuation of the associated pruritogen-induced pain responses. This could explain the decreased sensitivity to itch provocations previously observed in patients with chronic pain. SIGNIFICANCE: This study shows that the neuronal sensitization processes underlying the development secondary hyperalgesia involve significant gating of histaminergic as well as non-histaminergic pruriceptive transmission. Because these itch provocations normally target specific subpopulations of C-nociceptors they could be of relevance for exploratory purposes in pain patients.

Antipruritic effect of pretreatment with topical capsaicin 8% on histamine- and cowhage-evoked itch in healthy volunteers: a randomized, vehicle-controlled, proof-of-concept trial.

BACKGROUND: Chronic itch is difficult to treat. Low-concentration topical capsaicin (0·006-0·05%) has previously been applied in itch therapy but evidence on its efficacy is contradictory. OBJECTIVES: This vehicle-controlled, double-blinded study investigated the effect of topical capsaicin 8% after 1- and 24-h application on evoked itch, neurogenic inflammation and itch-associated dysaesthesia. METHODS: Sixteen healthy volunteers (aged 22 ± 0·5 years, nine female) were treated with capsaicin for 1 h and 24 h, and vehicle for 24 h on each volar forearm. Subsequently, histamine (1%, administered prick test lancets) and cowhage (40-45 spicules) were applied to the pretreated areas. Evoked itch and pain intensities were recorded for 10 min using a visual analogue scale (0-10 cm), while sensitivity to touch-evoked itch was evaluated using von Frey filaments before and after itch provocations. Neurogenic inflammation was assessed using perfusion imaging. RESULTS: In the vehicle areas peak itch responses to histamine and cowhage were 4·67 ± 0·58 and 5·15 ± 0·71, respectively. Capsaicin pretreatment reduced peak itch responses to histamine and cowhage after 24-h pretreatment to 1·41 ± 0·58 (P = 0·003) and 0·81 ± 0·18, (P < 0·001), respectively. Capsaicin pretreatment for 1 h reduced only cowhage-induced itch (P = 0·023). Furthermore, 24-h capsaicin pretreatment abolished punctuate hyperknesis and lowered histamine-induced neurogenic inflammation but did not affect weal reactions. CONCLUSIONS: Topical capsaicin 8% pretreatment for 24 h reduced histaminergic and nonhistaminergic itch by about 75%, while a significant reduction (≈60%) was achieved for only nonhistaminergic itch in a standard 1-h treatment. Further investigations are needed to elucidate the clinical potential of high-concentration capsaicin as an antipruritic.

Conditioning pain stimulation does not affect itch induced by intra-epidermal histamine pricks but aggravates neurogenic inflammation in healthy volunteers.

This study investigated whether itch induced by intra-epidermal histamine is subjected to modulation by a standardized conditioned pain modulation (CPM) paradigm in 24 healthy volunteers. CPM was induced by computer-controlled cuff pressure algometry and histamine was introduced to the volar forearm by skin prick test punctures. Moreover, neurogenic inflammation and wheal reactions induced by histamine and autonomic nervous system responses (heart rate variability and skin conductance) were monitored. CPM did not modulate the intensity of histamine-induced itch suggesting that pruriceptive signaling is not inhibited by pain-recruited endogenous modulation, however, CPM was found to aggravate histamine-induced neurogenic inflammation, likely facilitated by efferent sympathetic fibers.

Somatosensory and vasomotor manifestations of individual and combined stimulation of TRPM8 and TRPA1 using topical L-menthol and trans-cinnamaldehyde in healthy volunteers.

BACKGROUND: Activation of TRPM8 and TRPA1 receptors generates cold and cold pain sensations, respectively, and is presumably important in clinical pain manifestations, such as cold hyperalgesia. This study investigated the interaction between TRPM8 and TRPA1 receptors through stimulation of glabrous human skin (volar forearm) by topical administration of 40% L-menthol and 10% trans-cinnamaldehyde (CA), individually and in combination. METHODS: Sensory manifestations were assessed in 10 healthy volunteers via a platform of 11 quantitative sensory (thermal and mechanical stimuli) and vasomotor tests (skin temperature, perfusion and axon-reflex-flare) in a double-blinded randomized crossover design. RESULTS: Cold pain threshold was increased (p < 0.01, cold allodynia) by L-menthol alone and L-menthol + CA in combination but unaffected by CA. Mechanical pain threshold was significantly decreased (mechanical hyperalgesia) by all three substances (p < 0.01), with a significant intergroup difference found between CA alone and the less decreased L-menthol + CA (p < 0.05). Application of CA alone and L-menthol + CA in combination showed an increase in skin temperature and perfusion significantly larger than that induced by L-menthol alone (p < 0.05). An axon-reflex-flare was present after CA administration, but was significantly reduced upon addition of L-menthol (p < 0.01). CONCLUSION: This study elucidates the potential of L-menthol as a counter-irritant to secondary neurogenic inflammation and provides evidence of an intricate interplay between cold receptors TRPA1 and TRPM8, warranting further investigation of the neural coding of cold pain perception.

A review of topical high-concentration L-menthol as a translational model of cold allodynia and hyperalgesia.

BACKGROUND: Cold allodynia and cold hyperalgesia are both elusive features of neuropathic pain, particularly in patients with various polyneuropathies. Numerous studies have suggested that topical application of L-menthol causes temporary cold hypersensitivity and thus acts as a proxy for associated symptoms. This review summarizes studies on L-menthol-induced nociception, cold allodynia and cold hyperalgesia in vitro, in animals and in humans. METHODS: A comprehensive literature search was performed using the PubMed and Google Scholar databases until February 2013. Obtained manuscripts were reviewed for relevancy and reference lists of the retrieved articles were cross-checked for additional important studies. Solely the literature regarding topical application of L-menthol in humans was attained systematically. Of the total identified studies (96), 10 met the inclusion criteria being controlled studies applying L-menthol at a concentration of ≥ 30%. RESULTS: The extracted data are meticulously compared and presented with emphasis on clarity and transparency. In seven animal studies, cold allodynia or hyperalgesia was successfully established utilizing various methods. Eight studies in healthy volunteers unanimously reported a significant increase in cold pain threshold, representing cold allodynia and increased supra-threshold cold pain sensitivity, thus demonstrating cold hyperalgesia. CONCLUSIONS: Topical high-concentration L-menthol consistently induces cold hypersensitivity in animals and humans, thus constituting a predictable surrogate model of cold allodynia and hyperalgesia. Understanding translational features of this model and its underlying mechanisms could be valuable in preclinical and human phases of drug development and in improving current treatment of patients with polyneuropathy.

Ionization of helium and argon by very slow antiproton impact.

The total cross sections for single ionization of helium and single and double ionization of argon by antiproton impact have been measured in the kinetic energy range from 3 to 25 keV using a new technique for the creation of intense slow antiproton beams. The new data provide benchmark results for the development of advanced descriptions of atomic collisions and we show that they can be used to judge, for the first time, the validity of the many recent theories.

Stopping power in insulators and metals without charge exchange.

The slowing-down process of pointlike charged particles in matter has been investigated by measuring the stopping power for antiprotons in materials of qualitatively very different nature. Whereas the velocity-proportional stopping power observed for metal-like targets such as aluminum over a wide energy range of 1-50 keV is in agreement with expectations, it is surprising that the same velocity dependence is seen for a large band-gap insulator such as LiF. The validity of these observations is supported by several measurements with protons and several checks of the target properties. The observations call for both a qualitative explanation and a quantitative theoretical model.

Antiproton stopping at low energies: confirmation of velocity-proportional stopping power.

The stopping power for antiprotons in various solid targets has been measured in the low-energy range of 1-100 keV. In agreement with most models, in particular free-electron gas models, the stopping power is found to be proportional to the projectile velocity below the stopping-power maximum. Although a stopping power proportional to velocity has also been observed for protons, the interpretation of such measurements is difficult due to the presence of charge exchange processes. Hence, the present measurements constitute the first unambiguous support for a velocity-proportional stopping power due to target excitations by a pointlike projectile.

Maternal HLA class II allogenotypes are markers for the predisposition to fetal losses in families of women with unexplained recurrent fetal loss.

The HLA allogenotypes DR1/Br, DR3 and DR10 (entitled risk HLA markers) have been reported as being genetic markers for the predisposition to experience unexplained recurrent fetal losses. The aim of the study was to determine whether the putative risk HLA markers might also be markers for the risk of pregnancy loss in sisters and wives of brothers of women with unexplained recurrent fetal losses. Information concerning pregnancy outcomes among the relatives of 146 consecutive women with unexplained recurrent fetal losses was collected. Ninety-five of the full sisters, 69 of the full brothers and 50 of the wives of the brothers were HLA typed. Sisters who had experienced at least one previous pregnancy loss (affected women) shared more HLA haplotypes with the proband than unaffected sisters, when the proband was positive for the risk markers (P = 0.02). More affected than unaffected sisters and brothers' wives were positive for the risk markers (P < 0.005 and P < 0.03; respectively). The lowest estimate of the odds ratio for experiencing pregnancy loss among sisters and brothers' wives who were positive compared with those negative for the risk markers was 3.5 (95% credible interval = 1.9-5.8). It is concluded that maternal DR1/Br, DR3 and DR10 allogenotypes seem to be genetic markers for the risk of pregnancy loss among relatives of women with unexplained recurrent fetal losses. The pattern of inheritance suggests a polygenic mode of inheritance with alleles linked to the risk HLA markers interacting with non-HLA linked genes expressed on the fetus or the trophoblast.

[Index numbers of ambulatory care utilization. Methodical and content aspects of the value of survey data]. / Kennziffern zur ambulanten Inanspruchnahme. Methodische und inhaltliche Aspekte des Stellenwerts von Surveydaten.

Index numbers of the utilization of outpatient treatment are essential for differentiated health reporting. The established doctor fulfills nodal, coordinating and regulating functions. Therefore numbers reflecting those functions are also indicators for other types of health services. They allow conclusions about motives, preferences and attitudes of the population. Based on two representative population surveys (the Socio-economic Panel and the National Health Survey of the German Cardiovascular Prevention Study) the index numbers Quarterly-Utilization, Contact-Frequency and User-Frequency are analysed. Taking the example of age and sex differences the influence of differing research designs on the validity and possibility of interpretation of the different index numbers are discussed.

[The post-thrombotic syndrome. Description and comparison of diagnostic methods: clinical examination, venous return time, phlebography and ultrasonography]. / Det posttrombotiske syndrom. Beskrivelse og sammenligning af diagnostiske undersøgelsesmetoder: Klinisk undersøgelse, venøs returtid, flebografi og ultralyd.

Thirty-one patients with deep vein thrombosis (DVT) confirmed by phlebography 5-11 years previously were examined for the post-thrombotic syndrome (PTS). Where all of the patients were concerned, the examination included crossing-off of their symptoms of PTS on a special chart and clinical examination carried out by four doctors independently of one another, for 29 patients also determination of the venous return time by strain gauge pletysmography and for 29 patients also secondary phlebography (SF) and B-method ultrasonic scanning (UL). The degree of severity of PTS was determined by means of a scoring value which was calculated on the bases of four observers assessment of the clinical symptoms and findings. Significant differences were found for the clinical scores for legs with and without previous DVT, which shows that the method is of value despite a not inconsiderable interobserver variation. In the form employed here, pletysmography was found unsuitable for quantitating of PTS. In 60% of the patients, agreement was present between the clinical assessment, SF and UL. The necessity of agreement both as regards the diagnostic clinical criteria and as a measure for the degree of severity of PTS is emphasized. UL is recommended as a screening investigation for changes after DVT. Phlebography is only considered to be indicated in cases where detailed knowledge of the anatomical conditions is desired e.g. prior to venous surgery.

The relationship between ECG signs of atrial infarction and the development of supraventricular arrhythmias in patients with acute myocardial infarction.

ECGs obtained on arrival at the hospital from 277 patients with acute myocardial infarction were analyzed retrospectively for PR displacements, which were classified as major or minor criteria for atrial infarction and related to the later occurrence of supraventricular arrhythmia in the hospital. Major criteria were (1) PR segment elevation greater than 0.5 mm in leads V5 and V6 with reciprocal PR segment depression in leads V1 and V2, (2) PR segment elevation greater than 0.5 mm in lead I with reciprocal PR segment depression in leads II and III, and (3) PR segment depression greater than 1.5 mm in precordial leads and greater than 1.2 mm in leads I, II, and III. Abnormal P waves were classified as minor criteria. Major and minor criteria were found in 15 (5.4%) and 19 (6.9%) patients, respectively. Eight (53.3%) patients with major and six (31.6%) with minor criteria had supraventricular arrhythmias, giving odds ratios of 9.9 and 3.7, respectively. Enzyme-estimated infarct size, the occurrence of heart failure, and mortality rates did not differ in patients with or without major criteria for atrial infarction. We conclude that the occurrence of PR segment displacements on the admission ECG may predict the risk of developing supraventricular arrhythmias during hospitalization for myocardial infarction.

[Treatment of cardiac arrest. Recent aspects of cardiopulmonary resuscitation]. / Hjertestopbehandling. Nyere aspekter af kardiopulmonal genoplivning.

Opinions are still not unanimous about the mechanism behind circulation during external cardiac compression and this leads to uncertainty regarding the correct frequency, force of compression and its duration. Adrenaline and other alpha-stimulators increase blood flow during external cardiac compression and increase survival. Cardiac arrest results in anaerobic metabolism and combined metabolic and respiratory acidosis. On account of relatively low minute volume during external cardiac compression decrease in end-tidal carbon dioxide concentration is observed together with arterial alkalosis on account of hyperventilation and venous acidosis. No communications exist about the favourable effect of administration of bicarbonate during cardiac arrest. On the other hand, several conditions suggest that bicarbonate increases the intracellular acidosis with poorer possibilities for resuscitation with this form of treatment. Ischaemia results inter alia in intracellular accumulation of calcium which initiates potential cell destructive processes. No investigations are available which favour employment of calcium during cardiac arrest. Conversely animal experiments suggest the possibility of favourable effects from calcium-entry blockers. Ischaemia and, in particular, reperfusion release cell and vessel damaging free oxygen redicals. Intensive investigations are being conducted at present about the value of anti-oxidants for cerebral and myocardial protection.