Stimulation of the histamine 4 receptor upregulates thymic stromal lymphopoietin (TSLP) in human and murine keratinocytes.

The cytokine thymic stromal lymphopoietin (TSLP) is involved in the development and the progression of allergic diseases. It is mainly released by epithelial cells at barriers such as skin and gut in response to danger signals. Overexpression of TSLP in keratinocytes (KC) can provoke the development of a type 2 inflammatory response. Additionally, TSLP directly acts on sensory neurons and thereby triggers itch. Since histamine is also increased in lesions of inflammatory skin diseases, the aim of this study was to investigate possible effects of histamine as well as different histamine receptor subtype agonists and antagonists on TSLP production in KC. We therefore stimulated human KC with histamine in the presence or absence of the known TSLP-inductor poly I:C and measured TSLP production at protein as well as mRNA level. Histamine alone did not induce TSLP production in human KC, but pre-incubation with histamine prior to challenge with poly I:C resulted in a significant increase of TSLP production compared to stimulation with poly I:C alone. Experiments with different histamine receptor agonists (H1R: 2-pyridylethylamine; H2R: amthamine; H2R/H4R: 4-methylhistamine (4MH)) revealed a dominant role for the H4R receptor, as 4-MH in combination with poly I:C displayed a significant increase of TSLP secretion, while the other agonists did not show any effect. The increase in TSLP production by 4MH was blocked with the H4R antagonist JNJ7777120. This effect was reproducible also in the murine KC cell line MSC. Taken together, our study indicates a new role for the H4 receptor in the regulation of TSLP in keratinocytes. Therefore, blocking of the H4R receptor in allergic diseases might be promising to alleviate inflammation and pruritus via TSLP.

Capsaicin and sensory neurones: a historical perspective.

Capsaicin, the pungent ingredient of red pepper has become not only a "hot" topic in neuroscience but its new target-related unique actions have opened the door for the drug industry to introduce a new chapter of analgesics. After several lines of translational efforts with over 1,000 patents and clinical trials, the 8% capsaicin dermal patch reached the market and its long-lasting local analgesic effect in some severe neuropathic pain states is now well established. This introductory chapter outlines on one hand the historical background based on the author's 50 years of experience in this field and on the other hand emphasizes new scopes, fascinating perspectives in pharmaco-physiology, and molecular pharmacology of nociceptive sensory neurons. Evidence for the effect of capsaicin on C-polymodal nociceptors (CMH), C-mechanoinsensitive (CHMi), and silent C-nociceptors are listed and the features of the capsaicin-induced blocking effects of nociceptors are demonstrated. Common and different characteristics of nociceptor-blocking actions after systemic, perineural, local, intrathecal, and in vitro treatments are summarized. Evidence for the misleading conclusions drawn from neonatal capsaicin pretreatment is presented. Perspectives opened from cloning the capsaicin receptor "Transient Receptor Potential Vanilloid 1" (TRPV1) are outlined and potential molecular mechanisms behind the long-lasting functional, ultrastructural, and nerve terminal-damaging effects of capsaicin and other TRPV1 agonists are summarized. Neurogenic inflammation and the long-list of "capsaicin-sensitive" tissue responses are mediated by an unorthodox dual sensory-efferent function of peptidergic TRPV1-expressing nerve terminals which differ from the classical efferent and sensory nerve endings that have a unidirectional role in neuroregulation. Thermoregulatory effects of capsaicin are discussed in detail. It is suggested that since hyperthermia and burn risk due to enhanced noxious heat threshold are the major obstacles of some TRPV1 antagonists, they could be overcome. The special "multisteric" gating function of the TRPV1 cation channel provides the structural ground for blocking chemical activation of TRPV1 without affecting its responsiveness to physical stimuli. A new chapter of potential analgesics targeting nociceptors is now already supported for pain relief in persistent pathological pain states.

Early quality assessment lessens pheromone specificity in a moth.

Pheromone orientation in moths is an exemplar of olfactory acuity. To avoid heterospecific mating, males respond to female-produced blends with high specificity and temporal resolution. A finely tuned sensory to projection neuron network secures specificity, and this network is thought to assess pheromone quality continually during orientation. We tested whether male moths do indeed evaluate each pheromone encounter and surprisingly found that male European corn borer moths instead generalize across successive encounters. Although initially highly ratio specific, once "locked on" to the pheromone plume the acceptable ratio can vary widely, and even unattractive blends can become attractive. We further found that this "mental shortcut" may be a consequence of the fact that sensory neurons exposed to frequent encounters do not reliably encode blend ratios. Neurons tuned to either of the two pheromone components adapt differentially in plumes containing the preferred blend ratio (97:3) and cause the olfactory sensory signal to "evolve," even in narrowly tuned pheromonal circuits. However, apparently the brain interprets these shifting signals as invariant "gestalts." Generalization in pheromone perception may mitigate stabilizing selection and allow introgression between sympatric strains, such as in the European corn borer, that otherwise appear isolated by pheromonal differences. Generalization may also be important in responses to general odorants, as circuits underlying these display vast sensitivity differences, complex interactions, and temporal intricacies.

Up-regulation of tetrodotoxin-sensitive sodium currents by prostaglandin E2 in type-4 rat dorsal root ganglion cells.

Mechanisms were studied by which prostaglandin E(2) (PGE(2)) up-regulates Na(+) currents (INa) in medium diameter dorsal root ganglion (DRG) cells that express large T-type Ca(2+) currents (type-4 DRG cells). PGE(2) or the adenylyl cyclase (AC) activator forskolin (10 µM) up-regulated peak INa evoked by test potentials (TP) to -10 mV by an average of 13.5% and 21.8%, respectively. The PGE(2) and forskolin induced up-regulation of INa, evoked with TPs to -10 mV, began approximately 15-20 s after initiation of drug exposure and continued gradually over the course of 2-3 min. Both PGE(2) and forskolin significantly increased peak conductance without significantly shifting the voltage at which INa was ½ activated (V(a)) or ½ steady state inactivated. However, although V(a) was not significantly shifted, both PGE(2) and forskolin induced a proportionally greater percent increase in conductance at weak TPs to around -30 mV compared to stronger TPs to around 10 mV. The PGE(2)-induced up-regulation of INa was occluded by prior up-regulation with forskolin, and the up-regulation of INa by both PGE(2) and forskolin was blocked by Rp-cAMPs and 50 nM tetrodotoxin (TTX). In the presence of Rp-cAMPs, both PGE(2) and forskolin induced decreases in INa that peaked around 25 s following initiation of PGE(2)/forskolin application. The decrease induced by PGE(2) averaged 8.5%, which was significantly greater than the average 3.5% decrease induced by forskolin. Estimation of kinetic rate constants by fitting INa with a Markov channel state model, suggested that both PGE(2) and forskolin up-regulated INa by changing channel gating rather than by increasing channel number or unitary conductance. The data suggest that application of PGE(2) may initially induce a relatively rapid down-regulation of TTX-sensitive INa (signaling pathway uncharacterized), followed by a gradual up-regulation of INa via activation of an AC/PKA-dependent signaling pathway. The up-regulation of INa in sensory neurons with type-4 cell bodies may increase excitability and strengthen signaling, and may play some role in the allodynia and hyperalgesia associated with injury to nerves and peripheral tissues.

Spatial and temporal assessment of orofacial somatosensory sensitivity: a methodological study.

AIMS: To evaluate the sensitivity and reproducibility of a multimodal psychophysical technique for the assessment of both spatial and temporal changes in somatosensory function after an infraorbital nerve block. METHODS: Sixteen healthy volunteers with a mean (+/- SD) age of 22.5 +/- 3.4 years participated in 2 identical experimental sessions separated by 2 weeks. The subjects rated the perceived intensity of standardized nonpainful tactile, painful pinprick, warm, and cold stimuli applied to 25 points in 5 x 5 matrices in the infraorbital region of each side. The reproducibility of single points was tested, and a mean difference of 1.4 +/- 0.5 was found. A 0-50-100 numerical rating scale (NRS) with 50 denoting "just barely painful" was used. A modified ice hockey mask with adjustable settings was developed as a template to allow stimulation of the same points in the 2 sessions. Assessment of somatosensory function was carried out before the injection (baseline) and after 30 and 60 minutes on both the anesthetized and contralateral (control) side. In addition, the applicability of the psychophysical techniques was tested in pilot experiments in 2 patients before maxillary osteotomy and 3 months afterward. RESULTS: The overall analysis of mean NRS scores, number of points, and center-of-gravity coordinates for all stimulus modalities showed no significant main effects of session. Post-hoc tests for all stimulus modalities demonstrated significantly lower mean NRS scores and significantly more points (hyposensitivity) at 30 and 60 minutes postinjection compared to baseline values on the injection side (Tukey tests: P < .002). In the 2 maxillary osteotomy patients, the psychophysical techniques could successfully be applied, and bilateral hyposensitivity to all stimulus modalities was demonstrated at the 3-month follow-up. CONCLUSION: The present findings indicate that the psychophysical method is sufficiently reproducible, with no major differences between sessions in healthy subjects. All stimulus modalities demonstrated adequate sensitivity. Furthermore, measurement of points in 5 x 5 matrices allowed a spatial description of somatosensory sensitivity. This method may be valuable for studies on changes in somatosensory sensitivity following trauma or orthognathic surgery on the maxilla.

An assessment of short-acting hypnotics.

Insomnia, the experience of poor quality or quantity of sleep, is a very common complaint. Approximately 65 million adults (36% of the American population) complain of poor sleep, and of this group, 25% have insomnia on a chronic basis. These chronic insomniacs not only report higher rates of difficulty with concentration, memory and the ability to cope with minor irritations but also have 2.5 times more fatigue-related automobile accidents than do good sleepers. Despite its ubiquity, insomnia is often either untreated or inadequately treated. Short-acting hypnotics are advocated for transient insomnia, which lasts less than 3 weeks, and in patients with chronic insomnia as an adjunctive treatment where nonpharmacological treatment is not sufficient to alleviate insomnia and the related daytime detrimental effects. The putative adverse effects of hypnotics must be weighted against the severe health effects caused by continued sleep impairment. If hypnotic agents are used, they should be taken nightly only for brief use, or intermittently in longer term use. Benzodiazepines, zolpidem and zopiclone (in countries where the latter is available) remain the recommended hypnotic agents, although in the past few years there has been much criticism in lay magazines and on television about the use of benzodiazepines. However, this review of the efficacy and tolerability data of the short-acting hypnotics suggests that triazolam is comparable with other short-acting hypnotics at equipotent doses while taking into consideration that for every hypnotic, different study populations display different degrees of efficacy. In addition, contrary to previous suggestions that such adverse effects are rebound insomnia and anterograde amnesia are unique to triazolam, hypnotically equivalent doses of tirazolam have not been shown to produce these effects more frequently than other short-acting hypnotics. The newer nonbenzodiazepine hypnotics seem to be equally efficacious as the short-acting benzodiazepines; whether they will truly have a better adverse effect profile will be determined as more clinical experience accumulates. Despite the availability, relative safety and efficacy of these newer hypnotic agents, they should not be perceived as the sole treatment for insomnia and should be used in conjunction with nonpharmacological techniques (such as adherence to good sleep hygiene, sleep restriction, stimulus control and biofeedback therapy).

Assessment of exposure to arsenic among smelter workers: a five-year follow-up.

In a group of 43 smelter workers exposed to inorganic arsenic dust for 13-45 years, nerve conduction velocities (NCVs) were significantly lower in two peripheral nerves as compared with matching referents. With multivariate data analysis, a significant negative correlation was found between cumulative absorption of arsenic and NCV in four examined nerves and the sural amplitude. Clinical symptoms of neuropathy and other symptoms related to arsenic exposure were moderate, though the difference between the groups was significant. The mean total absorption of arsenic was calculated to be less than 5 g, and the maximal absorption about 20 g. These data indicate that the adverse effect of arsenic on the peripheral nerves is dependent on long-term exposure rather than on short-term fluctuations in exposure levels.

The importance of sensory nerve endings as sites of drug action.

The role that sensory nerve endings can play in drug action and the strategy used for its experimental analysis and proof is first exemplified by three effects of nicotine which are seen when the lowest effective doses of the drug are given intravenously in the cat: (1) a vasopressor effect due to arterial chemoreceptor stimulation; (2) a triad of bradycardia, hypotension and apnea, and (3) a depressant effect upon somatic motor activity, both of which are traced to vagal afferent endings in the pulmonary circulation. While receptors in the lung are responsible at least for the initial phase of the reflex responses listed in (2) and (3), sensory endings in heart, aorta, and carotid sinus region may be recruited into action as the drug reaches them. Several of these reflex effects can also be elicited by other sensory stimulant agents such as phenyldiguanide, 5-hydroxytryptamine, and veratrum alkaloids. In the second part, a general outline is given of what may be classified as 'Afferent Pharmacology', dealing with drug action upon sensory receptors and with the resulting remote drug effects. The action upon sensory receptors can either be a direct one ('primary' drug effect) consisting of stimulation, sensitization, desensitization, depression or combinations thereof, or an indirect ('secondary') effect brought about by a variety of drug-induced changes in the tissues surrounding the receptors. Depending on the nature of the primary or secondary action, the remote drug effect can be either an initiation, modification or impairment of those reflexes which have their origin in the sensory endings acted upon. Indeed, the grossly observable pharmacological actions of 'afferent drugs' are generally those relating to the reflex response. To avoid blurring of the boundaries of afferent pharmacology, drugs acting on central synapses of reflex pathways, or on the elaborate efferent control system of afferent input, are not included. A discussion follows of the topics of investigation, the influence of experimental conditions and anesthesia, various approaches and methods, the physiological and pharmacological importance of inquiry in this area, and some of the therapeutic aspects. Finally, brief mention is made of certain features and problems which appear to be characteristic of afferent pharmacology.