Functional brain alterations in symptomatic dermographism patients-An exploratory magnetoencephalography study.

Symptomatic dermographism (SD) is a common form of urticaria, which is triggered by stroking the skin. Brain involvement in its aetiology was investigated by means of magnetoencephalography (MEG) after provocation with histamine and dermography. Wheals were induced by histamine skin prick test and dermography in twelve SD patients and fourteen controls. Itch severity was scored on a Visual Analogue Scale (VAS). Relative power and functional connectivity (FC) were measured using a 306-channel whole-head MEG system at baseline and 10 min after histamine and dermography, and contrasted between groups and conditions. Furthermore, wheal diameter and itch scores after these procedures were correlated with the MEG values. SD patients had higher itch scores after histamine and dermography. No significant group-differences were observed in relative power or FC for any condition. In both groups, power decreases were mostly observed in the beta band, and power increases in the alpha bands, after provocation, with more regions involved in patients compared to controls. Increased FC was seen after histamine in patients, and after dermography in controls. In patients only, dermography and histamine wheal size correlated with the alpha2 power in the regions of interest that showed significant condition effects after these procedures. Our findings may be cautiously interpreted as aberrant itch processing, and suggest involvement of the central nervous system in the aetiology of SD.

Histamine- and pruritogen-induced itch is inhibited by a TRPM8 agonist: a randomized vehicle-controlled human trial.

BACKGROUND: Allergies often present challenges in managing itch and the effects of histamine. Cooling agents that act via transient receptor potential melastatin 8 (TRPM8) agonism have shown potential in itch management. However, animal studies on itch have limitations, as animals cannot communicate subjective events and their fur-coated skin differs from that of humans. Human studies offer more direct and reliable information. OBJECTIVES: To investigate the effects of a specific TRPM8 agonist gel (cryosim-1) on itch induced by various pruritogens in human skin. METHODS: Calcium imaging experiments determined the binding of cryosim-1 and histamine to their respective receptors. Thirty healthy volunteers underwent skin prick tests with pruritogens and a control vehicle. Itch and pain intensity were measured using a numerical rating scale (NRS) across 10 min. Participants were randomly assigned to pretreatments with vehicle or TRPM8 agonist gel. Tests were repeated at a later date, and skin moisture, transepidermal water loss and mechanical sensitivity were measured. RESULTS: The in vitro study confirmed that histamine is not a TRPM8 agonist and cryosim-1 does not act as an agonist or antagonist on the human histamine 1 receptor. The TRPM8 agonist gel significantly reduced the itch intensity for all pruritogens compared with the vehicle-only gel. It also reduced itch NRS and the integrated itch score. Mechanical sensitivity was also reduced. CONCLUSIONS: The specific TRPM8 agonist gel effectively suppressed human skin itch induced by various pruritogens. These versatile actions suggest that cooling agents may be promising treatments for multiple forms of itch stimuli.

Managing itching and the effects of histamine can be difficult for people with allergies. Cooling the skin or applying menthol provides some relief from itch, but the way they work is not fully understood. Cooling agents interact with a protein called TRPM8 (also known as the 'cold and menthol receptor') and have shown potential for the management of itch. However, much of the research has been done on animals and has limitations when compared with human studies. Antihistamine medications can help with histamine-induced itching, but they may not work for other causes of itch. This study investigated the effects of a specific TRPM8 agonist (a chemical that activates a receptor to produce a biologic response) gel called cryosim-1 on itch in human skin. To do this, we conducted tests on 30 healthy people using five different substances that cause itching. Participants rated the itch intensity and pain using a scale and we measured various aspects of their skin. The results showed that all substances caused significant itching compared to a control substance, but itchiness gradually decreased over time. Histamine and compound 48/80 also caused pain. However, when participants applied the TRPM8 activator gel before exposure, they experienced less itching and lower itch intensity versus the gel without the activator. There were no significant differences in pain between the TRPM8 activator and the gel without it. In summary, our findings showed that activating TRPM8 receptors with a specific substance effectively relieved itching caused by various irritants on human skin. This suggests its potential as a treatment for itch-related conditions. Further research is needed to understand its mechanisms better and evaluate its effectiveness in real-life situations.

Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus.

The cellular and molecular mechanisms mediating histamine-independent itch in primary sensory neurons are largely unknown. Itch induced by chloroquine (CQ) is a common side effect of this widely used antimalarial drug. Here, we show that Mrgprs, a family of G protein-coupled receptors expressed exclusively in peripheral sensory neurons, function as itch receptors. Mice lacking a cluster of Mrgpr genes display significant deficits in itch induced by CQ but not histamine. CQ directly excites sensory neurons in an Mrgpr-dependent manner. CQ specifically activates mouse MrgprA3 and human MrgprX1. Loss- and gain-of-function studies demonstrate that MrgprA3 is required for CQ responsiveness in mice. Furthermore, MrgprA3-expressing neurons respond to histamine and coexpress gastrin-releasing peptide, a peptide involved in itch sensation, and MrgprC11. Activation of these neurons with the MrgprC11-specific agonist BAM8-22 induces itch in wild-type but not mutant mice. Therefore, Mrgprs may provide molecular access to itch-selective neurons and constitute novel targets for itch therapeutics.

Topical Antiedematogenic Activity of the Essential Oil of Psidium brownianum Mart. (OEPB) in Murine Ear Edema Models.

Psidium brownianum Mart is reported in the literature by antinociceptive and antioxidant activities, indicating that this species' secondary metabolites might be used to control inflammatory processes. The present study aimed to characterize the topical antiedematogenic activity of the essential oil of Psidium brownianum Mart. (OEPB) in ear edema models by different inflammatory agents. Female Swiss mice (25-35 g) and Wistar albino rats (200-300 g) were used throughout tests (n=6/group) on acute or chronic edema models induced by single and multiple topical applications. The OEPB is administered topically pure or at a concentration of 100 or 200 mg/mL. The antiedematogenic mechanism of OEPB was analyzed by administering capsaicin, arachidonic acid, histamine, and phenol at the best effective dose (200 mg/mL). The results showed a significant reduction of edema-induced single (28.87 %) and multiple (50.13 %) applications of croton oil compared to the negative control group. Regarding potential mechanisms of action, OEPB (200 mg/mL) inhibited the development of edema triggered by capsaicin (29.95 %), arachidonic acid (22.66 %), phenol (23.35 %), and histamine (75.46 %), suggesting an interference with the histaminergic pathway. These results indicate that OEPB presents a topical antiedematogenic effect in acute and chronic murine models, possibly interfering with inflammatory pathways triggered by mediators such as histamine.

Enhancement of receptor-mediated calcium responses by phenytoin through the suppression of calcium excretion in human gingival fibroblasts.

BACKGROUND AND OBJECTIVES: Gingival overgrowth caused by phenytoin is proposed to be associated with Ca2+ signaling; however, the mechanisms that increase the intracellular Ca2+ concentration ([Ca2+ ]i ) are controversial. The current study aimed to elucidate the mechanism underlying the phenytoin-induced increase in [Ca2+ ]i in human gingival fibroblasts (HGFs). METHODS: Effects of 100 µM phenytoin on [Ca2+ ]i in HGFs were examined at the single-cell level using fluorescence images of fura-2 captured by an imaging system consisting of an EM-CCD camera coupled to an inverted fluorescence microscope at room temperature. RESULTS: Exposure of HGFs to 100 µM phenytoin induced a transient increase in [Ca2+ ]i in the absence of extracellular Ca2+ , indicating that the phenytoin-induced increase in [Ca2+ ]i does not require an influx of extracellular Ca2+ . In addition, phenytoin increased [Ca2+ ]i in HGFs depleted of intracellular Ca2+ stores by thapsigargin, indicating that neither Ca2+ release from stores nor inhibition of Ca2+ uptake is involved. Furthermore, the phenytoin-induced [Ca2+ ]i elevation was reduced to 18.8% in the absence of extracellular Na+ , and [Ca2+ ]i elevation upon removal of extracellular Na+ was reduced to 25.9% in the presence of phenytoin. These results imply that phenytoin increases [Ca2+ ]i of HGFs by suppressing the Na+ /Ca2+ exchanger. Suppression of intracellular Ca2+ excretion is thought to enhance the Ca2+ responses induced by various stimuli. Analysis at the single-cell level showed that stimulation with 1 µM ATP or 3 µM histamine increased [Ca2+ ]i in 20-50% of cells, and [Ca2+ ]i increased in many unresponsive cells in the presence of phenytoin. CONCLUSION: Our findings demonstrate that phenytoin induced increase in [Ca2+ ]i by the inhibition of Ca2+ efflux in HGFs. It was also found that phenytoin strongly enhanced small Ca2+ responses induced by stimulation with a low concentration of ATP or histamine by inhibiting Ca2+ efflux. These findings suggest a possibility that phenytoin causes drug-induced gingival overgrowth by interacting with inflammatory bioactive substances in the gingiva.

Antiedematogenic and Analgesic Activities of Abietic Acid in Mice.

Exacerbated inflammatory responses to harmful stimuli can lead to significant pain, edema, and other complications that require pharmacological intervention. Abietic acid (AA) is a diterpene found as a significant constituent in pine species, and evidence has identified its biological potential. The present study aimed to evaluate abietic acid's antiedematogenic and anti-inflammatory activity in mice. Swiss mice (Mus musculus) weighing 20-30 g were treated with AA at 50, 100, and 200 mg/kg. The central nervous system (CNS) effects were evaluated using open-field and rotarod assays. The antinociceptive and anti-inflammatory screening was assessed by the acetic acid and formalin tests. The antiedematogenic activity was investigated by measuring paw edema induced by carrageenan, dextran, histamine, arachidonic acid, and prostaglandin, in addition to using a granuloma model. The oral administration of abietic acid (200 mg/Kg) showed no evidence of CNS effects. The compound also exhibited significant antiedematogenic and anti-inflammatory activities in the carrageenan and dextran models, mostly related to the inhibition of myeloperoxidase (MOP) activity and histamine action and, to a lesser extent, the inhibition of eicosanoid-dependent pathways. In the granuloma model, abietic acid's effect was less expressive than in the acute models investigated in this study. In conclusion, abietic acid has analgesic and antiedematogenic activities related to anti-inflammatory mechanisms.

Modulating Effects of the Hydroethanolic Leaf Extract of Persicaria lanigera R. Br. Soják (Polygonaceae) against Acute Inflammation.

Plant species have been used traditionally to treat numerous inflammatory disorders because of their known medicinal properties. This study aimed to assess the anti-inflammatory effect of aqueous ethanolic leaf extract of Persicaria lanigera using acute inflammatory models. The safety profile of the Persicaria lanigera extract was assessed using an acute toxicity model. The anti-inflammatory effect of the Persicaria lanigera leaf extract (100-600 mg·kg-1, p.o.) was studied in carrageenan-induced paw oedema, zymosan-induced knee joint arthritis, and histamine-induced paw oedema in Sprague-Dawley rats (n = 5). It was observed that the Persicaria lanigera leaf extract administered prophylactically significantly inhibited paw oedema from 99.01 ± 12.59 to 59.10 ± 4.94%, 56.08 ± 3.65%, and 48.62 ± 3.27% at 100 mg·kg-1, 300 mg·kg-1, and 600 mg·kg-1, while the standard drug, aspirin, showed 41.84 ± 9.25% in carrageenan-induced paw oedema, respectively. Furthermore, the extract decreased knee joint inflammation significantly from 62.43 ± 5.73% to 32.07 ± 2.98% and 24.33 ± 8.58% at 300 mg·kg-1 and 600 mg·kg-1 in zymosan-induced knee joint inflammation, respectively. In the histamine-induced paw oedema model, the extract significantly inhibited oedema to 61.53 ± 9.17%, 54.21 ± 9.38%, and 54.22 ± 9.37% at the same doses. Aqueous ethanolic leaf extract of Persicaria lanigera is safe and attenuates inflammation in acute inflammation models.

Footedness for scratching itchy eyes in rodents.

The neural bases of itchy eye transmission remain unclear compared with those involved in body itch. Here, we show in rodents that the gastrin-releasing peptide receptor (GRPR) of the trigeminal sensory system is involved in the transmission of itchy eyes. Interestingly, we further demonstrate a difference in scratching behaviour between the left and right hindfeet in rodents; histamine instillation into the conjunctival sac of both eyes revealed right-foot biased laterality in the scratching movements. Unilateral histamine instillation specifically induced neural activation in the ipsilateral sensory pathway, with no significant difference between the activations following left- and right-eye instillations. Thus, the behavioural laterality is presumably due to right-foot preference in rodents. Genetically modified rats with specific depletion of Grpr-expressing neurons in the trigeminal sensory nucleus caudalis of the medulla oblongata exhibited fewer and shorter histamine-induced scratching movements than controls and eliminated the footedness. These results taken together indicate that the Grpr-expressing neurons are required for the transmission of itch sensation from the eyes, but that foot preference is generated centrally. These findings could open up a new field of research on the mechanisms of the laterality in vertebrates and also offer new potential therapeutic approaches to refractory pruritic eye disorders.

Nafamostat is a Potent Human Diamine Oxidase Inhibitor Possibly Augmenting Hypersensitivity Reactions during Nafamostat Administration.

Nafamostat is an approved short-acting serine protease inhibitor. However, its administration is also associated with anaphylactic reactions. One mechanism to augment hypersensitivity reactions could be inhibition of diamine oxidase (DAO). The chemical structure of nafamostat is related to the potent DAO inhibitors pentamidine and diminazene. Therefore, we tested whether nafamostat is a human DAO inhibitor. Using different activity assays, nafamostat reversibly inhibited recombinant human DAO with an IC50 of 300-400 nM using 200 µM substrate concentrations. The Ki of nafamostat for the inhibition of putrescine and histamine deamination is 27 nM and 138 nM, respectively For both substrates, nafamostat is a mixed mode inhibitor with P values of <0.01 compared with other inhibition types. Using 80-90% EDTA plasma, the IC50 of nafamostat inhibition was approximately 360 nM using 20 µM cadaverine. In 90% EDTA plasma, the IC50 concentrations were 2-3 µM using 0.9 µM and 0.18 µM histamine as substrate. In silico modeling showed a high overlap compared with published diminazene crystallography data, with a preferred orientation of the guanidine group toward topaquinone. In conclusion, nafamostat is a potent human DAO inhibitor and might increase severity of anaphylactic reaction by interfering with DAO-mediated extracellular histamine degradation. SIGNIFICANCE STATEMENT: Treatment with the short-acting anticoagulant nafamostat during hemodialysis, leukocytapheresis, extracorporeal membrane oxygenator procedures, and disseminated intravascular coagulation is associated with severe anaphylaxis in humans. Histamine is a central mediator in anaphylaxis. Potent inhibition of the only extracellularly histamine-degrading enzyme diamine oxidase could augment anaphylaxis reactions during nafamostat treatment.

Mild Skin Heating Evokes Warmth Hyperknesis Selectively for Histaminergic and Serotoninergic Itch in Humans.

Chronic itch can severely affect quality of life. Patients report that their chronic itch can be exacerbated by exposure to warm conditions ("warmth hyperknesis"). The aim of this mechanistic study was to investigate the effect of mild heating of the skin in humans on various experimental models of itch. A total of 18 healthy subjects were recruited to the study. Itch was provoked by histamine, serotonin, or cowhage in 3 different sessions. The provoked area was heated with an infrared lamp, and the skin temperature was either not altered, or was increased by 4°C or 7°C. Subsequent to induction of itch, the itch intensity was recorded for 10 min while the skin was heated continuously throughout the entire period of itch induction. Heating the skin resulted in a significant increase in itch intensity when provoked by histamine or serotonin. It is possible that thermoception and pruriception interact and selectively produce a higher itch intensity in histaminergic and serotoninergic itch.

Antipruritic Effect of Topical Acetaminophen Gel in Histaminergic and Non-histaminergic Itch Provocation: A Double-blind, Vehicle-controlled Pilot Study.

There is a need for new topical antipruritics that are effective on many types of itch. This study examined the antipruritic efficacy of a new formulation of topical acetaminophen. In vitro skin permeability studies showed that 2.5% and 5% formulations are able to rapidly deliver an adequate amount of the drug into the skin. In a double-blind, vehicle-controlled, randomized study in 17 healthy volunteers, 1%, 2.5% and 5% acetaminophen gels and a vehicle gel were applied to the skin prior to histaminergic and non-histaminergic itch induction and assessment of thermal pain thresholds. The 2.5% and 5% gel formulations significantly reduced the itch intensity time course and the area under the curve for both histamine and cowhage itch. No effect was noted on heat pain thresholds and no adverse effects were observed. These results suggest that topical acetaminophen would be a safe and effective over-the-counter medication for itch.

Evaluation of anti-inflammatory and analgesic effects of Hertia intermedia (Boiss.) Kuntze extract.

Hertia intermedia is a traditional medicinal plant of Balochistan, used for pain management and stomach problems. Current research work was intended to evaluate the anti-inflammatory and analgesic activities of crude ethanolic extract of H. intermedia. Anti-inflammatory activity was determined by the carrageenan-induced and histamine-induce Rat paw edema in rats, analgesic activity was determined by acetic acid-Induced writhing test, formalin-induced hind paw licking in mice and Tail immersion test. H. intermedia crude ethanolic extract showed significant (p<0.05) effect in both carrageenan and histamine-induced rat paw edema at both 250 and 500 mg/kg oral doses. There were significant analgesic activities in comparison with standard drug and control (p<0.05). It is concluded that H. intermedia crude ethanolic extract possesses significant anti-inflammatory and analgesic effects. However further studies may be carried out to isolate the phytochemicals responsible for anti-inflammatory and analgesic activities.

FGF13 Is Required for Histamine-Induced Itch Sensation by Interaction with NaV1.7.

Itch can be induced by activation of small-diameter DRG neurons, which express abundant intracellular fibroblast growth factor 13 (FGF13). Although FGF13 is revealed to be essential for heat nociception, its role in mediating itch remains to be investigated. Here, we reported that loss of FGF13 in mouse DRG neurons impaired the histamine-induced scratching behavior. Calcium imaging showed that the percentage of histamine-responsive DRG neurons was largely decreased in FGF13-deficient mice; and consistently, electrophysiological recording exhibited that histamine failed to evoke action potential firing in most DRG neurons from these mice. Given that the reduced histamine-evoked neuronal response was caused by knockdown of FGF13 but not by FGF13A deficiency, FGF13B was supposed to mediate this process. Furthermore, overexpression of histamine Type 1 receptor H1R, but not H2R, H3R, nor H4R, increased the percentage of histamine-responsive DRG neurons, and the scratching behavior in FGF13-deficient mice was highly reduced by selective activation of H1R, suggesting that H1R is mainly required for FGF13-mediated neuronal response and scratching behavior induced by histamine. However, overexpression of H1R failed to rescue the histamine-evoked neuronal response in FGF13-deficient mice. Histamine enhanced the FGF13 interaction with NaV1.7. Disruption of this interaction by a membrane-permeable competitive peptide, GST-Flag-NaV1.7CT-TAT, reduced the percentage of histamine-responsive DRG neurons, and impaired the histamine-induced scratching, indicating that the FGF13/NaV1.7 interaction is a key molecular determinant in the histamine-induced itch sensation. Therefore, our study reveals a novel role of FGF13 in mediating itch sensation via the interaction of NaV1.7 in the peripheral nervous system.SIGNIFICANCE STATEMENT Scratching induced by itch brings serious tissue damage in chronic itchy diseases, and targeting itch-sensing molecules is crucial for its therapeutic intervention. Here, we reveal that FGF13 is required for the neuronal excitation and scratching behavior induced by histamine. We further provide the evidence that the histamine-evoked neuronal response is mainly mediated by histamine Type 1 receptor H1R, and is largely attenuated in FGF13-deficent mice. Importantly, we identify that histamine enhances the FGF13/NaV1.7 interaction, and disruption of this interaction reduces histamine-evoked neuronal excitation and highly impairs histamine-induced scratching behavior. Additionally, we also find that FGF13 is involved in 5-hydroxytryptamine-induced scratching behavior and hapten 1-fluoro-2,4-dinitrobenzene-induced chronic itch.

Quantification of Trigeminovascular Hypersensitivity Using Laser Speckle Contrast Analysis in a Patient With Chronic Migraine.

BACKGROUND: Activation of peripheral and/or central trigeminovascular pain pathways are implicated in the pathogenesis of migraine. Small fibers mediate pain, thermal sensation, and autonomic functions. Axon flare response is correlated with local C-fiber activation and calcitonin gene-related peptide release. Laser speckle contrast analysis (LASCA) detects very subtle microcirculatory changes that are not visible to the naked eye. CASE: Axon flare response was elicited by 0.01 mL intradermal (i.d.) histamine introduced to the left forehead, trigeminal nerve ophthalmic branch (V1) skin area. Skin microvascular blood flow data were recorded using a LASCA real-time microcirculation imaging system. In the healthy control, prick stimulus slightly elevated focal skin microcirculation only at the stimulated focal area. However, in our patient with chronic migraine, the unilateral prick stimulation transiently (over 10 to 12 seconds) increased ipsilateral skin microcirculation at all 3 branches of the trigeminal nerve, with a slight expansion across the midline. Left V1 stimulation by i.d. histamine induced not only prominent but also long-lasting (10 to 15 minutes of recording time) axon flare response at the ipsilateral V1, V2, and V3 areas, with an expansion to the contralateral V1 area and without any report of allodynia or hyperalgesia. The treatment decreased axon flare characteristics probably by inhibiting neurogenic inflammation. DISCUSSION: The clinical characteristics and individual response to treatment vary widely across patients with pain. Here, we demonstrated the presence of transient spread of increased microcirculation at the ipsilateral trigeminal nerve, and also across the midline after prick stimulus, whereas a more prominent, widespread, and long-lasting histamine-induced axon flare response occurred in a rare subclass of patient who had chronic migraine with autonomic symptoms. The modulatory effect of the pharmacological intervention has also been objectively quantified by LASCA.

Safety, pharmacokinetics and pharmacodynamics of a novel anti-asthmatic drug, XC8, in healthy probands.

INTRODUCTION: XC8 (histamine glutarimide) is a novel agent which targets eosinophilic migration and mast cell degranulation and has shown anti-asthmatic effects in animal studies. OBJECTIVE: The objective of this placebo-controlled phase 1 study was to assess the safety of oral XC8 and to evaluate its pharmacokinetic and pharmacodynamic properties. METHODS: 32 healthy volunteers in three dose-escalation treatment groups (10 mg [n = 8], 50 mg [n = 8] and 200 mg [n = 16]) were randomized in a 3:1 ratio to XC8 or placebo respectively. The subjects received a single dose of the drug at Day 1 and then once-daily for 14 days (Days 8-21). RESULTS: No severe adverse events occurred. The number of adverse events was similar in the treatment arms compared to placebo and all subjects completed the study as planned. No clinically significant changes occurred in hematologic and biochemical blood tests in subjects receiving XC8. The pharmacokinetic data showed similar dose and time dependent mean plasma XC8 concentrations after single (Day 1) and multiple (Day 21) dosing. The mean maximum concentrations were 114-1993 ng/mL after single and 115-2089 ng/mL after multiple dosing. The mean times to maximum concentration were 0.68-1.01 and 0.67-0.98 h, respectively. There was no evidence for accumulation of XC8 after multiple dosing. CONCLUSION: XC8 was safe and well tolerated. A phase 2 study is being performed to further evaluate the potential role of XC8 in asthma treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02882217.

Effect of Diet in Chronic Spontaneous Urticaria: A Systematic Review.

Strategies for diets in chronic spontaneous urticaria (CSU) are controversial. This systematic review assessed the interest in diet for managing CSU. We searched for original reports in MEDLINE, EMBASE, CENTRAL and LILACS. Among the 278 reports screened, 20 were included, involving 1,734 patients. Reports described 3 types of systematic diet: pseudoallergen-free diet (n = 1,555 patients), low-histamine diet (n = 223) and diet without fish products (n = 47), which induced complete remission in 4.8%, 11.7% and 10.6% of patients, respectively, and partial remission in 37.0%, 43.9% and 4.3%. Eight reports described personalized exclusion diets (66 patients) adapted to symptoms/allergological test results and led to complete remission in 74.6% of patients, although the diagnosis of CSU was doubtful. No comparative randomized studies of diets were available. The only randomized studies were based on oral provocation tests with the suspected responsible diet. Population and outcomes were heterogeneous. In conclusion, there is evidence for the benefit of diets in CSU only in individual patients with clinical symptoms. However, the level of evidence is low for the benefit of systematic diets in CSU because systematic double-blind controlled trials of diet are lacking.

Effects of Short-term Temperature Change in the Innocuous Range on Histaminergic and Non-histaminergic Acute Itch.

While temperatures in the noxious range are well-known to inhibit acute itch, the impact of temperature in the innocuous temperature range is less well understood. We investigated the effect of alternating short-term temperature changes in the innocuous range on histamine and cowhage-induced acute itch, taking into account individual differences in baseline skin temperature and sensory thresholds. Results indicate that cooling the skin to the cold threshold causes a temporary increase in the intensity of histamine-induced itch, in line with previous findings. Skin warming increased cowhage-induced itch intensity. Potential mecha-nisms of this interaction between thermosensation and pruritoception could involve cold-sensitive channels such as TRPM8, TREK-1 or TRPC5 in the case of histamine. The rapid modulation of cowhage induced itch - but not histamine-induced itch - by transient skin warming could be related to the lower temperature threshold of pruriceptive polymodal C-fibres (cowhage) as compared to the higher temperature threshold of the mechanoinsensitive C-fibres conveying histaminergic itch.

Comparison of pruritus and sensory qualities induced by capsaicin, histamine and cowhage.

BACKGROUND: In skin diseases and experimental models of pruritus, pure itch is accompanied by additional sensations that are poorly characterized. OBJECTIVES: This study compared the sensory qualities evoked by different models of experimentally induced pruritus including skin prick testing (SPT) with histamine or capsaicin and application of cowhage spicules. SPT as a method of capsaicin application was validated for this purpose. METHODS: Two pilot experiments were performed in eight healthy volunteers. First, a concentration of 8% capsaicin was identified as evoking a reproducible itch using SPT. Further, a list of the seven most frequently reported sensations was chosen after SPT with 10 mg/mL histamine, 8% capsaicin and application of 40-45 cowhage spicules. Finally, 31 subjects were challenged with the same itch-inducers. Wheal and flare were measured at 10, 20, 40, 60 and 90 min, itch intensity every minute for 30 min, and the overall evaluation of sensory descriptors were recorded on a 100-mm visual analogue scale once itching had subsided. RESULTS: Skin prick testing with histamine and capsaicin resulted in flare reactions, which were 23% smaller for capsaicin (P < 0.001). Histamine, capsaicin and cowhage-induced pruritus, the duration of which was shorter for cowhage than for histamine (13.5 ± 1.4 vs. 8.8 ± 1.2 min, P = 0.005). Different mediators induced sensations of different intensities. Capsaicin produced less itch and physical urge to scratch than histamine (P = 0.001) and cowhage (P < 0.001). However, both capsaicin and cowhage induced more burning than histamine (P = 0.002 and P = 0.04, respectively). Provocation with cowhage caused more intense sensations of pricking than histamine (P = 0.033). CONCLUSION: This study shows that provocation with histamine, capsaicin and cowhage results in itch responses that are different in their duration, the profile of accompanying sensations, and the flare that comes with the itch.

Dose-dependent pruritogenic and inflammatory effects of intradermal injections of histamine, compound 48/80 and anti-canine IgE in healthy dogs.

BACKGROUND: Scratching behaviours associated with intradermal (i.d.) injection of pruritogens such as histamine and compound 48/80 into the skin of mice and humans is the commonly used model to advance itch research and drug development. The predictive validity of this model is poorly documented in dogs. OBJECTIVES: To evaluate the dose-dependent effects of pruritogenic substances, each with a different mechanism of action, in healthy dogs. ANIMALS: Ten healthy laboratory beagles. METHODS AND MATERIALS: All dogs were video-recorded for 30 min post-injection (mpi) of i.d. goat anti-canine IgE (4 and 25 µg/site), histamine and compound 48/80 (50, 100, 200, 400 µg/site); two buffered saline injections served as controls. Two blinded investigators reviewed the pruritic behaviours of all video recordings. Global wheal scores were evaluated at 30 min by a blinded investigator. RESULTS: All dogs showed wheal and erythema at the pruritogen injection site; global wheal scores at 30 min of each substance significantly increased at all concentrations compared to control (P ≤ 0.05). A blinded evaluation revealed that all pruritogens induced mild acute pruritic behaviours at the site of injection. There was no injection site pain seen in any dog. Compared to controls, injections of pruritogens did not significantly affect the pruritic seconds or occurrence of pruritic episodes for any of the substances. CONCLUSIONS AND CLINICAL SIGNIFICANCE: These preliminary results suggest that i.d. injections of the studied pruritogens can induce cutaneous wheal and flare response in healthy dogs; but inconsistencies occur in the induction of itch, even with the different concentrations of pruritogens.

Diphenhydramine pharmacokinetics after oral and intravenous administration of diphenhydramine and oral administration of dimenhydrinate to healthy dogs, and pharmacodynamic effect on histamine-induced wheal formation: a pilot study.

BACKGROUND: Histamine type-1 (H1) receptor antagonists such as diphenhydramine are frequently used for treatment of pruritus in dogs, yet therapeutic efficacy for allergic disorders is reported to be highly variable. Dimenhydrinate is a salt of diphenhydramine and 8-chlorotheophylline, and has been reported to produce superior oral absorption of diphenhydramine. HYPOTHESIS/OBJECTIVE: To determine the pharmacokinetic and pharmacodynamic properties of diphenhydramine in dogs after intravenous (1 mg/kg) and oral (5 mg/kg) administration, and when given orally as dimenhydrinate at a dose of 10 mg/kg (≈5 mg/kg diphenhydramine). ANIMALS: Each drug was administered to six healthy, fasted mixed-breed dogs in a research facility, using a cross-over design. METHODS AND MATERIALS: Blood samples were collected for pharmacokinetic analysis of diphenhydramine and chlorotheophylline at defined intervals. Pharmacodynamic response was measured by histamine-mediated cutaneous wheal formation. RESULTS: There was great variability in the data and one dog was an extreme outlier. The mean systemic availabilities of diphenhydramine were 7.8% and 22.0% after oral administration of diphenhydramine and dimenhydrinate, respectively, whereas the mean maximum concentrations were 36 (± 20) and 124 (± 46) ng/mL. The terminal elimination half-lives of diphenhydramine and dimenhydrinate were 5.0 (± 7.1) and 11.6 (± 17.7) h, respectively. Plasma diphenhydramine concentrations did not correlate with the percentage reduction in histamine-induced wheal formation. Theophylline reached plasma concentrations considered to be therapeutic for dogs. CONCLUSION: Oral absorption of diphenhydramine was approximately three times greater with a longer half-life when it was administered as the combination product dimenhydrinate.