Cutaneous Neurogenic Inflammation Research Articles

Further Exploring the Brain–Skin Connection: Stress Worsens Dermatitis via Substance P-dependent Neurogenic Inflammation in Mice

A neurogenic component in atopy and allergy is evident and potentially of great pathogenic relevance. Stress was recently shown to activate elements of this component and is vividly discussed as a cause of exacerbation. However, to date, scientific proof of stress-induced neuronal plasticity and neuro-immune interaction in atopy or allergy remains lacking. Here we show early evidence that exposure to sound stress and atopic dermatitis-like allergic dermatitis (AD) equipotently raise the number of cutaneous nerve fibers containing the prototypic stress neuropeptide substance P (SP) in mice. Stress increases AD readout parameters by at least 30% (eosinophil infiltration, vascular cell adhesion molecule-positive blood vessels, epidermal thickness). This dramatic pathologic exacerbation is associated with increased neurogenic inflammation (degranulated mast cells; interstitial neuropeptidergic dense core granules, mast cell apoptosis, endothelial gaping). Key features of AD exacerbation could not be induced in mice lacking the neurokinin-1 SP receptor (NK1). Interestingly, stress had no significant additional effect on CD4+ cell number, but shifted the cytokine profile toward TH2 in skin. Thus, we conclude that stress primarily exacerbates AD via SP-dependent cutaneous neurogenic inflammation and subsequent local cytokine shifting and should be considered as a therapeutic target, while it offers a convincing pathogenic explanation to affected patients and their frustrated physicians alike.

Roles of TRPV1 and Neuropeptidergic Receptors in Dorsal Root Reflex-Mediated Neurogenic Inflammation Induced by Intradermal Injection of Capsaicin

BackgroundAcute 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.ResultsHere 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 μg. 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.ConclusionOur 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.

The role of neuropeptides in psoriasis

The pathogenesis of psoriasis is incompletely understood but cutaneous neurogenic inflammation is probably involved. This involvement is suggested by a number of clinical and histological observations. Reports about the distribution of cutaneous nerves and the quantification of nerve growth factor and neuropeptides, including calcitonin gene-related peptide and vasoactive intestinal peptide, in lesional and nonlesional psoriatic skin suggest that sensory neuropeptides contribute to the development of psoriasis. This review summarizes what is known about the role of neurogenic markers in psoriasis.

Characteristic alterations of cutaneous neurogenic factors in photoaged skin

Although it has been recognized that photoageing and chronological ageing differ in various morphological and biological aspects, the characteristic alterations of cutaneous neurogenic factors in photoaged skin are poorly characterized. To characterize cutaneous neurogenic factors, including innervation, neuropeptides, nerve growth factor and interactions of mast cells, in photoaged skin. Paired biopsy specimens were obtained from sun-exposed volar forearm skin and from sun-protected dorsal upper arm skin of 20 elderly subjects. Various cutaneous neurogenic factors, including innervation, neuropeptides, neurokinin receptor, nerve growth factor, neurogenic inflammation and morphology of mast cells, were compared in sun-exposed vs. sun-protected skin quantitatively and qualitatively. Cutaneous neurogenic factors associated with photoageing were characterized by a significant increase in the densities of dermal and intraepidermal nerve fibres, a correlation between epidermal innervation and the severity of photodamage, increases in the number of neuropeptidergic sensory nerve fibres in the dermis and in tissue levels of sensory neuropeptides, increases in the content of nerve growth factor, reduced expression of neurokinin receptor 1 by epidermal keratinocytes and by vascular endothelial cells and a tachykinin-specific reduction of cutaneous neurogenic inflammation. Mast cells in photodamaged skin showed several characteristic morphological features, including various degrees of activation and an intimate association with fibroblasts, which were distinct from those in sun-protected skin. Furthermore, mast cells in photodamaged skin possessed larger amounts of substance P within their granules than did those in sun-protected skin. These findings document for the first time characteristic alterations of cutaneous neurogenic factors in photodamaged skin and suggest that the cutaneous nervous system may be involved in photoageing processes.

Prurigo nodularis: A review

Prurigo nodularis is a chronic condition characterized by a papulonodular pruriginous eruption of unknown aetiology. This condition is a difficult disease to treat and causes frustration to both the patient and the treating doctor. A variety of systemic conditions have been reported to be associated with prurigo nodularis. The mechanism by which these disorders may trigger prurigo nodularis is unknown. Nerve growth factor has been implicated in the pathogenesis of prurigo nodularis. Calcitonin gene-related peptide and substance P immunoreactive nerves are markedly increased in prurigo nodularis when compared with normal skin. These neuropeptides may mediate the cutaneous neurogenic inflammation and pruritus in prurigo nodularis. Topical or intralesional glucocorticoids are the treatment of choice. Other topical treatments such as topical vitamin D3, and topical capsaicin have also been reported to be effective. Oral treatments such as cyclosporin and thalidomide have been shown to improve both appearance of the skin and pruritus. We review the clinical features, associations, pathology, pathogenesis and treatment of prurigo nodularis.

Attenuation of acute experimental colitis by preventing NPY Y1 receptor signaling

Neuropeptide Y (NPY), a 36-amino acid peptide, is widely expressed in the central and peripheral nervous system. NPY is involved in the regulation of several physiological processes, including energy balance, food intake, and nociception. Recently, we showed that activation of the NPY Y1 receptor is required for cutaneous neurogenic inflammation. Because neurogenic inflammation could participate in colitis, the aim of this study was to investigate the role of the NPY Y1 receptor in acute colitis using mice genetically deficient of NPY Y1 receptor. In addition, the Y1 receptor antagonist H409/22, was also investigated. Animals received 5% dextran sulfate sodium (DSS) in drinking water for 7 days. One group of animals also received the Y1 receptor antagonist, administered intraperitoneally twice daily. Disease activity was assessed daily for 7 days in all groups. DSS induced colitis in all animals resulting in weight loss, diarrhea, epithelial damage, crypt shortening, and inflammatory infiltration. However, clinical manifestation of the disease was markedly attenuated in Y1 null mutant mice as well as in mice receiving the Y1 antagonist. Histological analysis showed that tissue damage and ulceration were less severe in Y1-deficient animals. Consistent with the clinical and histological data, capsaicin-induced plasma extravasation was significantly reduced in the gut of Y1 null mutant animals compared with treated wild-type animals. These data indicate that NPY and Y1 receptor are involved in intestinal inflammation and suggest that inhibition of NPY Y1 receptor signaling may provide a novel therapeutic approach in the treatment of colonic inflammation.

The neuropeptide PACAP upregulates expression and release of cytokines and cell adhesion molecules in human microvascular endothelial cells via VPAC type 1 receptor

Pituitary adenylate cyclase‐activating peptide (PACAP) and vasoactive intestinal peptide (VIP) belong to the same superfamily of neuropeptides which exert their effects by activating G‐protein‐coupled receptors defined as PACAP. So far, three receptor subtypes exist (PAC1R, VPACR‐1 and VPACR‐2). Because, PACAP appears to play a crucial role in cutaneous inflammation and vasoregulation, we examined the expression and biological effects of this peptide in primary human dermal microvascular endothelial cells (HDMECs). We detected the expression of PACAP and VPAC type 1 receptor at RNA and protein level by RT‐PCR and immunohistochemistry, indicating an autocrine regulatory mechanism. cAMP assays revealed VPAC1R to be functional in these cells. RT‐PCR showed upregulation of IL‐8 in a time‐ and dose‐dependent manner. ELISA experiments confirmed release of IL‐8 by HDMEC cells. We also investigated cell adhesion molecule expression after stimulation with PACAP. ICAM‐1 mRNA was upregulated at 3 and 6 h after treatment with PACAP, while VCAM was only upregulated maximally at 6 h after PACAP stimulation, indicating the regulation of cell adhesion molecule expression in human dermal endothelial cells via VPAC1R. Immunoreactivity for VPAC‐1R was enhanced in microvascular endothelial cells of patients with atopic dermatitis and urticaria, indicating upregulation of this receptor in endothelial cells during cutaneous inflammation. In summary, VIP and PACAP may play an important role in cutaneous neurogenic inflammation by activating VPAC‐1R on dermal microvascular endothelial cells.

Proteinase‐activated receptor‐2 mediates itch: a novel pathway for pruritus in human skin

Proteinase‐activated receptors are G‐protein‐coupled receptors with seven‐transmembrane domains activated by serine proteinases. PAR‐2 is a receptor for mast cell tryptase, house dust mite allergens, bacterial antigens and trypsin, for example, indicating a role of PAR‐2 during inflammation and immune responses. In the skin, PAR‐2 is expressed by keratinocytes, endothelial cells, certain immune cells and nerves, suggesting a broad regulatory role of proteases in the skin. Recently, PAR‐2 has been demonstrated to be involved in neurogenic inflammation. Therefore, we examined whether neuronal PAR‐2 may be involved in pruritus of human skin. The endogenous PAR‐2 agonist tryptase was increased up to fourfold in atopic dermatitis (AD) patients. PAR‐2 was markedly enhanced on primary afferent nerve fibres in skin biopsies of AD patients. Intracutaneous injection of endogenous PAR‐2 agonists provoked enhanced and prolonged itch when applied intralesionally. Interestingly, itch upon mast cell degranulation prevailed despite local antihistamines in AD patients only. Thus, we identified enhanced PAR‐2 signalling as a new link between inflammatory and sensory phenomena in AD patients. PAR‐2 antagonists, thus, represent a promising therapeutic target for the treatment of cutaneous neurogenic inflammation and pruritus.

Involvement of peripheral neuropeptide y receptors in sympathetic modulation of acute cutaneous flare induced by intradermal capsaicin

In a recent study, we have demonstrated that the dorsal root reflex (DRR)-mediated acute cutaneous neurogenic inflammation following intradermal injection of capsaicin (CAP) is sympathetically dependent and subject to modulation by peripheral α 1-adrenoceptors. Postganglionic sympathetic neurons contain not only adrenergic neurotransmitters, but also non-adrenergic substances, including neuropeptide Y (NPY). In this study, we examined if peripheral NPY receptors participate in the flare following CAP injection. Different NPY receptor subtypes were studied by using relatively specific agonists and antagonists for the Y 1 and Y 2 subtypes. Changes in cutaneous blood flow on the plantar surface of the foot were measured using a laser Doppler flowmeter. Following CAP injection, cutaneous flare spread more than 20 mm away from the site of CAP injection. Removal of the postganglionic sympathetic nerves by surgical sympathectomy reduced dramatically the CAP-evoked flare. If the foot of sympathectomized rats was pretreated with either NPY or Y 2 receptor agonists by intra-arterial injection, the spread of flare induced by CAP injection could be restored and prolonged. However, if the spinal cord was pretreated with a GABA A receptor antagonist, bicuculline, to prevent DRRs, NPY or an Y 2 receptor agonist no longer restored the CAP-evoked flare. A Y 1 receptor agonist did not affect the CAP-evoked flare in sympathectomized rats. In sympathetically intact rats, blockade of either peripheral NPY or Y 2 receptors with [ d-Trp 32]-NPY or BIIE0246 markedly reduced the flare induced by CAP injection, whereas blockade of peripheral Y 1 receptors by BIBP3226 did not obviously affect the flare. It is suggested that NPY is co-released with NE from the postganglionic sympathetic terminals to activate NPY Y 2 and α 1 receptors following CAP injection. Both substances are involved, at least in part, in modulation of the responses of CAP sensitive afferents thereby affecting their ability to evoke the release of inflammatory agents from primary afferents.

Modern aspects of cutaneous neurogenic inflammation.

Recent findings have shed new light on the role of peripheral nerves in the skin and established a modern concept of cutaneous neurobiology. Closely related monodirectional and/or bidirectional pathways exist in which the central and peripheral nervous system, the endocrine and immune system, and almost all skin cells are involved. Information is emerging about the factors involved in these immunomodulatory mechanisms, which are defined as neuropeptides, neurotransmitters, neurotrophins, and neurohormones. The interaction between peripheral nerves and the immune system is mediated by different types of cutaneous nerve fibers that release neuromediators and activate specific receptors on target cells in the skin such as keratinocytes, mast cells, Langerhans cells, microvascular endothelial cells, fibroblasts, and infiltrating immune cells. These interactions influence a variety of physiologic and pathophysiologic functions including cellular development, growth, differentiation, immunity, vasoregulation, leukocyte recruitment, pruritus, and wound healing. A variety of mechanisms lead to the termination of cellular responses to released neuropeptides under physiologic circumstances. Herein, we highlight some of the recent advances of neurocutaneous biology and discuss the role of nerves in mediating cutaneous inflammation. Understanding the mechanisms and the factors controlling neuromediators and their receptors and degrading enzymes will lead to the identification of novel therapeutic targets for the treatment of cutaneous diseases.

Proteinase-Activated Receptor-2 Mediates Itch: A Novel Pathway for Pruritus in Human Skin

We examined whether neuronal proteinase-activated receptor-2 (PAR-2) may be involved in pruritus of human skin. The endogenous PAR-2 agonist tryptase was increased up to fourfold in atopic dermatitis (AD) patients. PAR-2 was markedly enhanced on primary afferent nerve fibers in skin biopsies of AD patients. Intracutaneous injection of endogenous PAR-2 agonists provoked enhanced and prolonged itch when applied intralesionally. Moreover, itch upon mast cell degranulation was abolished by local antihistamines in controls but prevailed in AD patients. Thus, we identified enhanced PAR-2 signaling as a new link between inflammatory and sensory phenomena in AD patients. PAR-2 therefore represents a promising therapeutic target for the treatment of cutaneous neurogenic inflammation and pruritus.

Sympathetic modulation of acute cutaneous flare induced by intradermal injection of capsaicin in anesthetized rats.

Much of the acute cutaneous neurogenic inflammation after intradermal injection of capsaicin (CAP) in rats is mediated by dorsal root reflexes (DRRs), which cause the release of inflammatory agents from primary afferent terminals. Sympathetic efferents modulate neurogenic inflammation by interaction with primary afferent terminals. In this study, we examined if DRR-mediated flare after CAP injection is subject to sympathetic modulation. Changes in cutaneous blood flow on the plantar surface of the foot were measured using a laser Doppler flow meter. After CAP injection, cutaneous flare spread more than 20 mm away from the site of CAP injection. However, this CAP-induced flare was significantly reduced after surgical sympathectomy. Decentralization of postganglionic neurons did not affect the flare induced by CAP injection. If the foot of sympathectomized rats was pretreated with an alpha(1)-adrenoceptor agonist (phenylephrine) by intra-arterial injection, the spread of flare induced by CAP injection could be restored. However, if the spinal cord was pretreated with a GABA(A) receptor antagonist, bicuculline, to prevent DRRs, phenylephrine no longer restored the CAP-evoked flare. An alpha(2)-adrenoceptor agonist (UK14,304) did not affect the CAP-evoked flare in sympathectomized rats. In sympathetically intact rats, blockade of peripheral alpha(1)-adrenoceptors with terazosin profoundly reduced the flare induced by CAP injection, whereas blockade of peripheral alpha(2)-adrenoceptors by yohimbine did not obviously affect the flare. Therefore the pathogenesis of acute neurogenic inflammation in the intradermal CAP injection model depends in part on intact sympathetic efferents and alpha(1)-adrenoceptors. Peripheral alpha(1)-adrenoceptors thus modulate the ability of capsaicin sensitive afferents to evoke the release of inflammatory agents from primary afferents by DRRs.

Activation of spinal ORL-1 receptors prevents acute cutaneous neurogenic inflammation: role of nociceptin-induced suppression of primary afferent depolarization

Neurogenic inflammation is an inflammatory response of peripheral tissue to vasoactive substances released from sensory afferent terminals. It can be triggered via a local axon reflex and by dorsal root reflex (DRR) activity involving the spinal cord. Nociceptin, an endogenous ligand for the opioid receptor-like (ORL-1) G-protein coupled receptor, has been found to inhibit the local axon reflex-mediated neurogenic inflammation by suppressing the release of vasoactive neuropeptides from sensory afferent terminals. The present study was to explore the role of spinal ORL-1 receptors in the modulation of DRR-induced neurogenic inflammation. We first examined the effect of nociceptin on DRR by recording dorsal root potentials (DRPs) and the associated antidromic discharges, evoked by electrical stimulation of an adjacent dorsal root in an in vitro neonatal rat spinal cord preparation. Nociceptin reversibly inhibited the DRP in a concentration-dependent manner (IC 50: ∼45 nM, maximal inhibition: ∼50%), an effect that was antagonized by the ORL-1 receptor antagonist, J-113397. Neurochemical studies demonstrated that nociceptin (10 μM) also produced an ∼40% reduction in gamma amino butyric acid (GABA) release evoked by electrical stimulation of neonatal rat spinal cord slices. On the other hand, nociceptin had no effect on exogenous GABA-evoked DRP. These findings suggest that the nociceptin-induced inhibition of the DRP is most likely due to the suppression of GABA release, the principle transmitter mediating DRP, from GABAergic neurons that are pre-synaptic to primary afferent terminals. Finally, in order to explore the physiological significance of such modulation in a fully integrated system, we evaluated the effect of intrathecally administered nociceptin on capsaicin-induced acute cutaneous neurogenic inflammation in rat hind paw, quantified by examining the degree of paw edema in anesthetized rats. The magnitude of capsaicin-induced increase of paw thickness was reduced by ∼50% from 31±1.34% ( n=6) to 15±1.63% ( n=8; P<0.05) by nociceptin (10 μmol). We conclude that spinal ORL-1 receptors can modulate neurogenic inflammation by suppressing the GABAergic neuronal activity in the dorsal horn that is responsible for generating DRRs.

Dorsal root reflexes and cutaneous neurogenic inflammation after intradermal injection of capsaicin in rats.

The role of dorsal root reflexes (DRRs) in acute cutaneous neurogenic inflammation induced by intradermal injection of capsaicin (CAP) was examined in anesthetized rats. Changes in cutaneous blood flow (flare) on the plantar surface of the foot were measured using a laser Doppler flowmeter, and neurogenic edema was examined by measurements of paw thickness. To implicate DRRs in neurogenic inflammation after CAP injection, the ipsilateral sciatic and femoral nerves were sectioned, dorsal rhizotomies were performed at L(3-)-S(1), and antagonists of GABA or excitatory amino acid receptors were administered intrathecally. Intradermal injection of CAP evoked a flare response that was largest at 15-20 mm from the injection site and that spread >30 mm. Acute transection of the sciatic and femoral nerves or dorsal rhizotomies nearly completely abolished the blood flow changes 15-20 mm from the CAP injection site, although there was only a minimal effect on blood flow near the injection site. These procedures also significantly reduced neurogenic edema. Intrathecal bicuculline, 6-cyano-7-nitroquinoxaline-2,3-dione, (CNQX) or D(-)-2-amino-7-phosphonoheptanoic acid (AP7), but not phaclofen, also reduced dramatically the increases in blood flow 15-20 mm from the CAP injection site, but had only a minimal effect on blood flow near the injection site. Neurogenic edema was reduced by the same agents that reduced blood flow. Multiunit DRRs recorded from the central stumps of cut dorsal rootlets in the lumbar spinal cord were enhanced after CAP injection. This enhanced DRR activity could be reduced significantly by posttreatment of the spinal cord with bicuculline, CNQX or AP7, but not phaclofen. It is concluded that peripheral cutaneous inflammation induced by intradermal injection of CAP involves central nervous mechanisms. DRRs play a major role in the development of neurogenic cutaneous inflammation, although a direct action of CAP on peripheral nerve terminals or the generation of axon reflexes also may contribute to changes in the skin near the injection site.

Effect of ultraviolet light on the release of neuropeptides and neuroendocrine hormones in the skin: mediators of photodermatitis and cutaneous inflammation.

Ultraviolet (UV) irradiation of the skin causes both inflammation and alterations in the skin immune system. There is increasing experimental evidence that UV-induced skin inflammation is influenced by the sensory nervous system and the neuroendocrine system in the skin. The resulting complex network of cytokines, chemokines, neuropeptides, neuropeptide-degrading enzymes, neurohormones, and other inflammatory mediators mediate photodermatitis and cutaneous inflammation. Neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) are released from sensory nerves innervating the skin upon UV exposure. In addition, a variety of cells in the skin produce increased neuroendocrine hormones such as proopiomelanocortin (POMC) peptides and their receptors as well as neurotrophins after UV exposure. Neuropeptides and neurohormones are capable of directly or indirectly mediating UV-induced cutaneous neurogenic inflammation by the induction of vasodilatation, plasma extravasation, and augmentation of UV-induced cytokine, chemokine, or cellular adhesion molecule expression required for activation and trafficking of inflammatory cells into the inflamed tissue. Neuropeptides and neurotrophins may also play a role in the repair of cutaneous UV injury. In addition to proinflammatory effects, UV-induced neuropeptides and neurohormones such as CGRP and alpha-melanocyte-stimulating hormone may have immunosuppressive effects in the skin. This review will focus on the role that SP, CGRP, POMC peptides, and their receptors may play in modulating UV-induced inflammation in the skin.

Neurogenic inflammation, vascular permeability, and mast cells. II. Additional evidence indicating that mast cells are not involved in neurogenic inflammation.

Activation of cutaneous sensory nerves induces vasodilatation and vascular permeability, i.e., neurogenic inflammation. We examined the histology and possible mast cell involvement in cutaneous neurogenic inflammation induced by electrical nerve stimulation (ENS). Three lines of evidence indicated that mast cells were not involved in rodent cutaneous neurogenic inflammation induced by electrical stimulation of the saphenous nerve. 1) Most mast cells (86.5% of all mast cells in the dorsal skin of the paw) were found in the deep dermis, whereas vessels developing increased vascular permeability after nerve stimulation (visualized with the supravital dye Monastral blue B, a macro-molecular tracer) were localized predominantly in the superficial dermis. By contrast, i.v. substance P, which also causes increased cutaneous vascular permeability, predominantly caused deeper vessels to leak. As analyzed by electron microscopy, the vessels that developed permeability in response to nerve stimulation, and were thereby stained with Monastral blue B, were found to be exclusively postcapillary venules. 2) Disodium cromoglycate (DSCG), a mast cell stabilizing compound, inhibited the cutaneous vascular permeability induced by intradermal injections of anti-IgE in a dose-dependent manner. By contrast, vascular permeability induced by ENS was not influenced by disodium cromoglycate treatment. 3) ENS and i.v. substance P both induced cutaneous vascular permeability in mast cell-deficient W/Wv mice, despite the fact that their skin contained only 4.7% of the mast cells present in their normal +/+ litter mates. The magnitude of ENS-induced vascular permeability responses in W/Wv mice were similar to control +/+ and BALB/c mice. This study supports our earlier observations suggesting that mast cell activation is not essential for the initial, vascular permeability phase of neurogenic inflammation in rodent skin.

Relationships between permeable vessels, nerves, and mast cells in rat cutaneous neurogenic inflammation

Electrical stimulation of rat sensory nerves produces cutaneous vasodilation and plasma protein extravasation, a phenomenon termed "neurogenic inflammation". Rat skin on the dorsum of the paw developed neurogenic inflammation after electrical stimulation of the saphenous nerve. In tissue sections, the extravasation of the supravital dye monastral blue B identified permeable vessels. Mast cells were identified by toluidine blue stain. Permeable vessels were significantly more dense in the superficial 120 microns of the dermis than in the deeper dermis, whereas mast cells were significantly more frequent in the deeper dermis. The relationships between nociceptive sensory nerve fibers, permeable vessels, and mast cells were examined by indirect immunohistochemistry for calcitonin gene-related peptide (CGRP), neurokinin A (NKA), and substance P (SP). CGRP-, NKA-, and SP-containing nerves densely innervated the superficial dermis and appeared to innervate the vessels that became permeable during neurogenic inflammation. In contrast, mast cells were not associated with either permeable vessels or nerve fibers. These data suggest that electrical stimulation of rat sensory nerves produces vascular permeability by inducing the release of neuropeptides that may directly stimulate the superficial vascular bed. Mast cells may not be involved in this stage of cutaneous neurogenic inflammation in rat skin.

The effect of capsaicin on cutaneous C-fibres, neurogenic inflammation and substance P levels in the rabbit

The effect of capsaicin on cutaneous C-fibres, neurogenic inflammation and substance P levels in the rabbit

Intracellular potential changes of primary afferent nerve fibers in spinal cords of cats.

ArticlesINTRACELLULAR POTENTIAL CHANGES OF PRIMARY AFFERENT NERVE FIBERS IN SPINAL CORDS OF CATSK. KoketsuK. KoketsuPublished Online:01 Sep 1956https://doi.org/10.1152/jn.1956.19.5.375MoreSectionsPDF (3 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited Byα5GABAA receptors mediate primary afferent fiber tonic excitability in the turtle spinal cordEmanuel Loeza-Alcocer, Martha Canto-Bustos, Justo Aguilar, Ricardo González-Ramírez, Ricardo Felix, and Rodolfo Delgado-Lezama1 November 2013 | Journal of Neurophysiology, Vol. 110, No. 9The Effects of Isoflurane on Conditioned Inhibition by Dorsal Column StimulationAnesthesia & Analgesia, Vol. 97, No. 2Periaqueductal gray-evoked dorsal root reflex is frequency dependentBrain Research, Vol. 976, No. 2Biphasic vasomotor reflex responses of the hand skin following intradermal injection of melittin into the forearm skin9 January 2012 | European Journal of Pain, Vol. 6, No. 6Differential effects of muscimol upon the firing frequency of large and small amplitude antidromic dorsal root action potentials in rat spinal cord in vitroNeuroscience Letters, Vol. 330, No. 2GABAA and 5-HT3 Receptors Are Involved in Dorsal Root Reflexes: Possible Role in Periaqueductal Gray Descending InhibitionYuan Bo Peng, Jing Wu, William D. Willis, and Daniel R. Kenshalo1 July 2001 | Journal of Neurophysiology, Vol. 86, No. 1Dorsal Root Reflexes and Cutaneous Neurogenic Inflammation After Intradermal Injection of Capsaicin in RatsQing Lin, Jing Wu, and William D. Willis1 November 1999 | Journal of Neurophysiology, Vol. 82, No. 5The dorsal root reflex in isolated mammalian spinal cordComparative Biochemistry and Physiology Part A: Physiology, Vol. 93, No. 1Demonstration of the synaptic origin of primary afferent depolarization (PAD) in the isolated spinal cord of the hamsterBrain Research, Vol. 341, No. 2An investigation of the dorsal root reflex using an in vitro preparation of the hamster spinal cordBrain Research, Vol. 331, No. 2Prolonged post-tetanic depolarization of frog dorsal root fibersNeuroscience, Vol. 9, No. 1Extracellular K+ accumulation in the central nervous systemProgress in Biophysics and Molecular Biology, Vol. 42Intra-axonal recordings in rat dorsal column axons: membrane hyperpolarization and decreased excitability precede the primary afferent depolarizationBrain Research, Vol. 238, No. 1Effects of morphine on human spinal cord and peripheral nervous activitiesPain, Vol. 8, No. 1Junctional mechanisms at group Ia synapsesProgress in Neurobiology, Vol. 12, No. 1Primary afferent depolarization: direct evidence in the trigeminal systemBrain Research, Vol. 75, No. 2Trigeminal PAD as disynaptically evoked by stimulation of the trigeminal sensory branchesBrain Research, Vol. 72, No. 2Studies on post-tetanic depression of the dorsal root reflex in the forelimb skin nerves of the catBrain Research, Vol. 63Primary afferent hyperpolarization without postsynaptic potentiationExperimental Neurology, Vol. 38, No. 2Intraspinal latency, cutaneous fiber composition, and afferent control of the dorsal root reflex in catBrain Research, Vol. 47, No. 2Dorsal root potentials in the chloralose-anesthetized catExperimental Neurology, Vol. 25, No. 3 More from this issue > Volume 19Issue 5September 1956Pages 375-392 https://doi.org/10.1152/jn.1956.19.5.375PubMed13367869History Published online 1 September 1956 Published in print 1 September 1956 Metrics