capsazepine and Neurogenic-Inflammation

Rosacea is a common chronic inflammatory skin condition that is often refractory to treatment, with frequent relapses. Alterations in the skin immunological response and Demodex mite infestation are the primary aetiologic factors targeted for treatment. Transient receptor potential cation channel subfamily V member 1 (TRPV1) is a nociceptive cation channel that plays a role in cutaneous neurogenic pain and can be activated by various rosacea triggers.. We investigated the effects of TRPV1 modulation in rosacea, focussing on Demodex mite colonization and cutaneous neurogenic inflammation.. We examined mRNA expression levels according to Demodex population counts. An in vitro study using capsazepine as a TRPV1 antagonist was performed to assess the influence of TRPV1 in keratinocytes. A rosacea-like mouse model was generated by the injection of the 37-amino acid C-terminal cathelicidin peptide (LL37), and changes in the skin, dorsal root ganglion (DRG) and ears were examined.. Increased Demodex mite population counts were associated with increased expression levels of TRPV1, tropomyosin receptor kinase A (TrkA) and nerve growth factor (NGF), and these levels could be reduced by capsazepine treatment in keratinocytes. In an in vivo study, the downstream effects of TRPV1 activation were investigated in the skin, DRG and ears of the rosacea-like mouse model.. The findings of this study are instrumental for understanding the underlying causes of rosacea and could potentially lead to the development of new treatments targeting the NGF-TrkA-TRPV1 pathway. The identification of this pathway as a therapeutic target could represent a major breakthrough for rosacea research, potentially resulting in more effective and targeted rosacea treatments. This study contributes to an improved understanding of rosacea pathophysiology, which may lead to the development of more effective treatments in the future.

Topics: Animals; Mice; Mite Infestations; Mites; Nerve Growth Factor; Neurogenic Inflammation; Rosacea; TRPV Cation Channels

To investigate the interaction and involvement of hydrogen sulfide and transient receptor potential vanilloid type 1 in the pathogenesis of sepsis. Hydrogen sulfide has been demonstrated to be involved in many inflammatory states including sepsis. Its contribution in neurogenic inflammation has been suggested in normal airways and urinary bladder. However, whether endogenous hydrogen sulfide would induce transient receptor potential vanilloid type 1-mediated neurogenic inflammation in sepsis remains unknown.. Prospective, experimental study.. Research laboratory.. Male Swiss mice.. Mice were subjected to cecal ligation and puncture-induced sepsis and treated with transient receptor potential vanilloid type 1 antagonist capsazepine (15 mg/kg subcutaneous) 30 mins before cecal ligation and puncture. To investigate hydrogen sulfide-mediated neurogenic inflammation in sepsis, DL-propargylglycine (50 mg/kg intraperitoneal), an inhibitor of hydrogen sulfide formation was administrated 1 hr before or 1 hr after the induction of sepsis, whereas sodium hydrosulfide (10 mg/kg intraperitoneal), a hydrogen sulfide donor, was given at the same time as cecal ligation and puncture. Lung and liver myeloperoxidase activities, liver cystathionine-gamma-lyase activity, plasma hydrogen sulfide level, histopathological examination, and survival studies were determined after induction of sepsis.. Capsazepine treatment attenuates significantly systemic inflammation and multiple organ damage caused by sepsis, and protects against sepsis-induced mortality. Similarly, administration of sodium hydrosulfide exacerbates but capsazepine reverses these deleterious effects. In the presence of DL-propargylglycine, capsazepine causes no significant changes to the attenuation of sepsis-associated systemic inflammation, multiple organ damage, and mortality. In addition, capsazepine has no effect on endogenous generation of hydrogen sulfide, suggesting that hydrogen sulfide is located upstream of transient receptor potential vanilloid type 1 activation, and may play a critical role in regulating the production and release of sensory neuropeptides in sepsis.. The present study shows that hydrogen sulfide induces systemic inflammation and multiple organ damage characteristic of sepsis via transient receptor potential vanilloid type 1-mediated neurogenic inflammation.

Topics: Alkynes; Animals; Capsaicin; Cystathionine gamma-Lyase; Glycine; Hydrogen Sulfide; Liver; Lung; Male; Mice; Multiple Organ Failure; Neurogenic Inflammation; Peroxidase; Sepsis; Sulfides; Transient Receptor Potential Channels; TRPV Cation Channels

Various volatile organic compounds (VOCs) act as a causative agent of skin inflammation. We investigated the effect of topical application of several VOCs and formalin on microvascular leakage in rat skin. We tested capsaicin, which is a reagent that specifically causes the skin response via endogenously released tachykinins. Evans blue dye extravasation served as an index of the increase in skin vascular permeability. After shaving the abdomen, we applied formalin, m-xylene, toluene, styrene, benzene, ethylbenzene, acetone, diethyl ether, hexane, heptane, cyclohexane and capsaicin to the skin. At 40min after application, skin samples were collected. Among all of the VOCs tested, all of the aromatic compounds significantly produced skin microvascular leakage that was similar to formalin and capsaicin. We also investigated the skin responses seen after the intravenous administration of CP-99,994 (1.5 or 5mg/kg), which is a tachykinin NK1 receptor antagonist, ketotifen (1 or 3mg/kg), which is a histamine H1 receptor antagonist that stabilizes the mast cells, and the topical application of capsazepine (22.5 or 50mM), which is the transient receptor potential vanilloid 1 (TRPV1) antagonist. The response induced by formalin and capsaicin was completely inhibited by CP-99,994. On the other hand, the antagonist partially reduced the response induced by m-xylene, toluene and styrene by 39%, 50% and 46%, respectively. Capsazepine and ketotifen did not alter the response induced by formalin or any of the aromatic compounds. Like capsaicin, formalin and the aromatic compounds at least partially caused skin microvascular leakage, which was due to tachykinin NK1 receptor activation related to the release of tachykinins from the sensory nerve endings. However, it is unlikely that mast cells and TRPV1 play an important role in the skin response.

Topics: Administration, Topical; Animals; Antipruritics; Capillary Leak Syndrome; Capsaicin; Cell Degranulation; Disinfectants; Dose-Response Relationship, Drug; Formaldehyde; Hydrocarbons, Aromatic; Ketotifen; Male; Mast Cells; Neurogenic Inflammation; Neurokinin-1 Receptor Antagonists; Piperidines; Rats; Rats, Wistar; Regional Blood Flow; Skin

Acute cutaneous neurogenic inflammation initiated by activation of transient receptor potential vanilloid-1 (TRPV1) receptors following intradermal injection of capsaicin is mediated mainly by dorsal root reflexes (DRRs). Inflammatory neuropeptides are suggested to be released from primary afferent nociceptors participating in inflammation. However, no direct evidence demonstrates that the release of inflammatory substances is due to the triggering of DRRs and how activation of TRPV1 receptors initiates neurogenic inflammation via triggering DRRs.. Here we used pharmacological manipulations to analyze the roles of TRPV1 and neuropeptidergic receptors in the DRR-mediated neurogenic inflammation induced by intradermal injection of capsaicin. The degree of cutaneous inflammation in the hindpaw that followed capsaicin injection was assessed by measurements of local blood flow (vasodilation) and paw-thickness (edema) of the foot skin in anesthetized rats. Local injection of capsaicin, calcitonin gene-related peptide (CGRP) or substance P (SP) resulted in cutaneous vasodilation and edema. Removal of DRRs by either spinal dorsal rhizotomy or intrathecal administration of the GABAA receptor antagonist, bicuculline, reduced dramatically the capsaicin-induced vasodilation and edema. In contrast, CGRP- or SP-induced inflammation was not significantly affected after DRR removal. Dose-response analysis of the antagonistic effect of the TRPV1 receptor antagonist, capsazepine administered peripherally, shows that the capsaicin-evoked inflammation was inhibited in a dose-dependent manner, and nearly completely abolished by capsazepine at doses between 30-150 mug. In contrast, pretreatment of the periphery with different doses of CGRP8-37 (a CGRP receptor antagonist) or spantide I (a neurokinin 1 receptor antagonist) only reduced the inflammation. If both CGRP and NK1 receptors were blocked by co-administration of CGRP8-37 and spantide I, a stronger reduction in the capsaicin-initiated inflammation was produced.. Our data suggest that 1) the generation of DRRs is critical for driving the release of neuropeptides antidromically from primary afferent nociceptors; 2) activation of TRPV1 receptors in primary afferent nociceptors following intradermal capsaicin injection initiates this process; 3) the released CGRP and SP participate in neurogenic inflammation.

Topics: Analgesics; Animals; Bicuculline; Calcitonin Gene-Related Peptide; Capsaicin; Edema; GABA Antagonists; Injections, Intradermal; Neurogenic Inflammation; Peptide Fragments; Rats; Receptors, Neurokinin-1; Reflex; Spinal Nerve Roots; Substance P; TRPV Cation Channels; Vasodilation

The mechanism by which Clostridium difficile toxin A causes substance P (SP) release and subsequent inflammation in the rat ileum is unknown. Pretreatment with the vanilloid receptor subtype 1 (VR1) antagonist, capsazepine, before toxin A administration significantly inhibited toxin A-induced SP release and intestinal inflammation. Intraluminal administration of the VR1 agonist capsaicin caused intestinal inflammation similar to the effects of toxin A. Pretreatment with capsazepine before capsaicin administration also significantly inhibited capsaicin-induced intestinal inflammation. These results suggest that intraluminal toxin A causes SP release from primary sensory neurons via stimulation of VR1 receptors resulting in intestinal inflammation.

Topics: Acute-Phase Reaction; Animals; Bacterial Toxins; Capsaicin; Clostridioides difficile; Dose-Response Relationship, Drug; Drug Interactions; Endocytosis; Enteritis; Enterotoxins; Ileum; Immunohistochemistry; Intestinal Secretions; Male; Neurogenic Inflammation; Neurons; Peroxidase; Rats; Receptors, Drug; Substance P; Time Factors

Many of the physiological hallmarks associated with neurogenic inflammatory processes in cutaneous tissues are similarly present within orofacial structures. Such attributes include the dependence upon capsaicin-sensitive sensory neurons and the involvement of certain inflammatory mediators derived therein, including calcitonin gene-related peptide (CGRP). However, there are also important differences between the trigeminal and spinal nervous systems, and the potential contributions of neurogenic processes to inflammatory disease within the trigeminal system have yet to be fully elucidated. We present here a model system that affords the ability to study mechanisms regulating the efferent functions of peptidergic terminals that may subserve neurogenic inflammation within the oral cavity. Freshly dissected buccal mucosa tissue from adult, male, Sprague-Dawley rats was placed into chambers and superfused with oxygenated, Krebs buffer. Serial aliquots of the egressing superfusate were acquired and analysed by radioimmunoassay for immunoreactive CGRP (iCGRP). Addition of the selective excitotoxin, capsaicin (10-300 microm), to the superfusion buffer resulted in a significant, concentration-dependent increase in superfusate levels of iCGRP. Similarly, release of iCGRP from the buccal mucosa could also be evoked by a depolarizing concentration of potassium chloride (50 mm) or by the calcium ionophore A23187 (1 microm). The specific, capsaicin receptor antagonist, capsazepine (300 microm), completely abolished the capsaicin-evoked release of iCGRP while having no effect whatsoever on the potassium-evoked release. Moreover, capsaicin-evoked release was dependent upon the presence of extracellular calcium ions and was significantly, though incompletely, attenuated by neonatal capsaicin denervation. Collectively, these data indicate that the evoked neurosecretion of iCGRP in response to capsaicin occurs via a vanilloid receptor-mediated, exocytotic mechanism. The model system described here should greatly facilitate future investigations designed to identify and characterize the stimuli that regulate the release of CGRP or other neurosecretory substances in isolated tissues. This system may also be used to elucidate the role of these mediators in the aetiology of inflammatory processes within the trigeminal field of innervation.

Topics: Animals; Bradykinin; Calcimycin; Calcitonin Gene-Related Peptide; Calcium; Capsaicin; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Histamine; Inflammation Mediators; Ionophores; Male; Mouth Mucosa; Neurogenic Inflammation; Nociceptors; Organ Culture Techniques; Pain Measurement; Potassium Chloride; Rats; Rats, Sprague-Dawley; Serotonin; Trigeminal Nerve