capsazepine and Pruritus

Two histamine receptor subtypes (HR), namely H1R and H4R, are involved in the transmission of histamine-induced itch as key components. Although exact downstream signaling mechanisms are still elusive, transient receptor potential (TRP) ion channels play important roles in the sensation of histaminergic and non-histaminergic itch. The aim of this study was to investigate the involvement of TRPV1 and TRPA1 channels in the transmission of histaminergic itch. The potential of TRPV1 and TRPA1 inhibitors to modulate H1R- and H4R-induced signal transmission was tested in a scratching assay in mice in vivo as well as via Ca

Topics: Acetanilides; Animals; Calcium; Capsaicin; Female; Ganglia, Spinal; Gene Expression; Histamine; Male; Methylhistamines; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Molecular Imaging; Primary Cell Culture; Pruritus; Purines; Ruthenium Red; Sensory Receptor Cells; Signal Transduction; TRPA1 Cation Channel; TRPV Cation Channels

There is a major clinical need for new therapies for the treatment of chronic itch. Many of the molecular components involved in itch neurotransmission are known, including the neuropeptide NPPB, a transmitter required for normal itch responses to multiple pruritogens in mice. Here, we investigated the potential for a novel strategy for the treatment of itch that involves the inhibition of the NPPB receptor NPR1 (natriuretic peptide receptor 1). Because there are no available effective human NPR1 (hNPR1) antagonists, we performed a high-throughput cell-based screen and identified 15 small-molecule hNPR1 inhibitors. Using in vitro assays, we demonstrated that these compounds specifically inhibit hNPR1 and murine NPR1 (mNPR1). In vivo, NPR1 antagonism attenuated behavioral responses to both acute itch- and chronic itch-challenged mice. Together, our results suggest that inhibiting NPR1 might be an effective strategy for treating acute and chronic itch.

Topics: Animals; Behavior, Animal; Cell-Free System; Dermatitis, Contact; Disease Models, Animal; Ganglia, Spinal; Humans; Mice, Inbred C57BL; Mice, Knockout; Neurons; Pruritus; Receptors, Atrial Natriuretic Factor; Reproducibility of Results; Signal Transduction; Small Molecule Libraries

The contributions of gasotransmitters to itch sensation are largely unknown. In this study, we aimed to investigate the roles of hydrogen sulfide (H2S), a ubiquitous gasotransmitter, in itch signaling. We found that intradermal injection of H2S donors NaHS or Na2S, but not GYY4137 (a slow-releasing H2S donor), dose-dependently induced scratching behavior in a μ-opioid receptor-dependent and histamine-independent manner in mice. Interestingly, NaHS induced itch via unique mechanisms that involved capsaicin-insensitive A-fibers, but not TRPV1-expressing C-fibers that are traditionally considered for mediating itch, revealed by depletion of TRPV1-expressing C-fibers by systemic resiniferatoxin treatment. Moreover, local application of capsaizapine (TRPV1 blocker) or HC-030031 (TRPA1 blocker) had no effects on NaHS-evoked scratching. Strikingly, pharmacological blockade and silencing of Cav3.2 T-type calcium channel by mibefradil, ascorbic acid, zinc chloride or Cav3.2 siRNA dramatically decreased NaHS-evoked scratching. NaHS induced robust alloknesis (touch-evoked itch), which was inhibited by T-type calcium channels blocker mibefradil. Compound 48/80-induced itch was enhanced by an endogenous precursor of H2S (L-cysteine) but attenuated by inhibitors of H2S-producing enzymes cystathionine γ-lyase and cystathionine β-synthase. These results indicated that H2S, as a novel nonhistaminergic itch mediator, may activates Cav3.2 T-type calcium channel, probably located at A-fibers, to induce scratching and alloknesis in mice.

Topics: Acetanilides; Animals; Behavior, Animal; Calcium Channel Blockers; Calcium Channels, T-Type; Capsaicin; Cystathionine beta-Synthase; Cystathionine gamma-Lyase; Disease Models, Animal; Diterpenes; Male; Mibefradil; Mice; Pruritus; Purines; Receptors, Opioid; RNA Interference; Sensory Receptor Cells; Sulfides; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPV Cation Channels

Noxious cold reduces pruritus and transient receptor potential ankyrin subfamily member 1 (TRPA1), a non-selective cation channel, is known as a noxious cold-activated ion channel. Recent findings implicated the involvement of TRPA1 in pain induced by endothelin-1 (ET-1). Therefore, we evaluated its potential role in pruritus induced by ET-1. We found that ruthenium red (RR; a nonselective TRP inhibitor) and AP18 (a TRPA1 antagonist) significantly increased scratching bouts caused by ET-1, while capsazepine (a TRPV1 antagonist) and morphine showed no effects in the ET-1-induced scratching response. However, RR and capsazepine significantly reduced scratching bouts caused by histamine. Our results suggested that activation of TRPA1 could suppress itch induced by ET-1 and this is not related to pain induced by ET-1.

Topics: Animals; Behavior, Animal; Capsaicin; Endothelin-1; Enzyme Inhibitors; Histamine; Irritants; Male; Mice; Mice, Inbred C57BL; Pruritus; Ruthenium Red; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPV Cation Channels

We investigated whether capsaicin induces itching in skin with existing inflammation. We induced skin inflammation by intradermal injection of complete Freund's adjuvant (CFA) in the neck of mice. Four days later, we injected capsaicin in the same area and counted the number of scratching bouts for 30 min. We examined potential effects on pain in parallel experiments in which CFA and capsaicin were intradermally injected into hind paws. We used the time spent licking the hind paws during the 15 min after capsaicin injection as an estimate of pain. Capsaicin injection into the skin pretreated with CFA, but not into healthy skin, induced scratching. The scratching behavior was reduced by pretreatment with naloxone or capsazepine, selective antagonists for transient receptor potential vanilloid receptor-1 (TRPV1), but not morphine or mepyramine, selective antagonists for histamine 1 receptor. In animals injected with capsaicin into the hind paws, licking behavior was significantly inhibited via a μ-receptor-dependent mechanism. Our results show that TRPV1 activation, which normally induces pain, evokes an itch-related response in the presence of inflammation. This model may be interesting for future studies to explore the mechanism of a painful stimuli-induced itch observed under pathological conditions.

Topics: Adjuvants, Immunologic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Capsaicin; Dimethyl Sulfoxide; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Freund's Adjuvant; Inflammation; Injections, Intradermal; Male; Mice; Mice, Inbred C57BL; Morphine; Naloxone; Pain; Pruritus; Receptors, Opioid, mu; Reflex; Sensory System Agents; Skin; Time Factors; TRPV Cation Channels

In patients with atopic dermatitis, alcoholic beverages can sometimes trigger or enhance itching. We have previously reported that HR-1 hairless mice fed a commercial special diet, HR-AD, but not a normal diet, develop atopic dermatitis-like skin inflammation with prolonged spontaneous scratching, and that skin barrier dysfunction is involved in the basal scratching. In the present study, the effects of ethanol on itch-related scratching were examined in this mouse model. When ethanol (30%, 10 ml/kg) was given orally to HR-AD-fed mice, scratching with long duration was further markedly increased, while oral ethanol administration had little effect on the scratching response in normal diet-fed mice. The scratching response after oral ethanol administration in HR-AD-fed mice (ethanol-induced scratching) was attenuated by antagonism of the mu-opioid receptor or local skin anesthesia, as in human itching. Ethanol-induced scratching was also suppressed by improvement of skin barrier function by an application of petrolatum ointment, while ethanol administration itself did not affect the function. This suggests that ethanol indirectly aggravates the basal scratching. Although antagonism of the transient receptor potential vanilloid-1 did not affect ethanol-induced scratching, blockade of ethanol actions in the central nervous system (CNS), including gamma-aminobutyric acid type A receptor antagonism and N-methyl-d-aspartate receptor activation, inhibited it. Taken together, the present study demonstrates that orally administered ethanol markedly aggravates itch-related scratching in HR-AD-fed mice developing atopic dermatitis, and suggests that the CNS depressant actions of ethanol play an important role in the aggravation.

Topics: Administration, Oral; Animals; Capsaicin; Dermatitis, Atopic; Dibucaine; Ethanol; Female; Mice; Mice, Hairless; N-Methylaspartate; Naltrexone; Petrolatum; Pruritus; Skin Temperature

Histamine is known to excite a subset of C-fibers and cause itch sensation. Despite its well-defined excitatory action on sensory neurons, intracellular signaling mechanisms are not understood. Previously, we demonstrated that bradykinin excited sensory neurons by activating TRPV1 via the phospholipase A(2) (PLA(2)) and lipoxygenase (LO) pathway. We, thus, hypothesized that histamine excited sensory neurons via the PLA(2)/LO/TRPV1 pathway. Application of histamine elicited a rapid increase in intracellular Ca(2+) ([Ca(2+)](i)) that desensitized slowly in cultured dorsal root ganglion neurons. Histamine-induced [Ca(2+)](i) was dependent on extracellular Ca(2+) and inhibited by capsazepine and by SC0030, competitive antagonists of TRPV1. Quinacrine and nordihydroguaiaretic acid, a PLA(2) and an LO inhibitor, respectively, blocked the histamine-induced Ca(2+) influx in sensory neurons, while indomethacin (a cyclooxygenase inhibitor) did not. We thus conclude that histamine activates TRPV1 after stimulating the PLA(2)/LO pathway, leading to the excitation of sensory neurons. These results further provide an idea for potential use of TRPV1 antagonists as anti-itch drugs.

Topics: Animals; Calcium; Calcium Signaling; Capsaicin; Cells, Cultured; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Ganglia, Spinal; Histamine; Lipoxygenase; Neurons, Afferent; Nociceptors; Phospholipases A; Pruritus; Rats; Receptors, Drug