Sensory C-fibers Research Articles

Aural Stimulation with Capsaicin Ointment Improved the Swallowing Function in Patients with Dysphagia: Evaluation by the SMRC Scale

Cough and swallowing reflexes are important airway-protective mechanisms against aspiration. Angiotensin-converting enzyme (ACE) inhibitors, one of the side effects of which is cough, have been reported to reduce the incidence of aspiration pneumonia in hypertensive patients with stroke. ACE inhibitors have also been reported to improve the swallowing function in post-stroke patients. On the other hand, stimulation of the Arnold nerve, the auricular branch of the vagus, triggers the cough reflex (Arnold's ear-cough reflex). Capsaicin, an agonist of Transient Receptor Potential Vanilloid 1 (TRPV1), has been shown to activate the peripheral sensory C-fibers. Stimulation of the sensory branches of the vagus in the laryngotracheal mucosa with capsaicin induces the cough reflex and has been reported to improve the swallowing function in patients with dysphagia. In our previous study, we showed that aural stimulation of the Arnold nerve with 0.025% capsaicin ointment improved the swallowing function, as evaluated by the endoscopic swallowing score, in 26 patients with dysphagia. In the present study, the video images of swallowing recorded in the previous study were re-evaluated using the SMRC scale by an independent otolaryngologist who was blinded to the information about the patients and the endoscopic swallowing score. The SMRC scale is used to evaluate four aspects of the swallowing function: 1) Sensory: the initiation of the swallowing reflex as assessed by the white-out timing; 2) Motion: the ability to hold blue-dyed water in the oral cavity and induce laryngeal elevation; 3) Reflex: glottal closure and the cough reflex induced by touching the epiglottis or arytenoid with the endoscope; 4) Clearance: pharyngeal clearance of the blue-dyed water after swallowing. Accordingly, we demonstrated that a single application of capsaicin ointment to the external auditory canal of patients with dysphagia significantly improved the R, but not the S, M or C scores, and this effect lasted for 60 min. After repeated aural stimulation with the ointment for 7 days, the R score improved significantly in patients with severe dysphagia. The present findings suggest that stimulation of the Arnold's branch of the vagus in the external auditory canal with capsaicin improves the glottal closure and cough reflex in patients with dysphagia. Thus, aural stimulation with capsaicin represents a novel treatment for dysphagia. It is also suggested that repeated alternative aural stimulation with capsaicin for a week, rather than a single application, is needed to improve the swallowing function in patients with severe dysphagia. By the same mechanism as that underlying the effect of ACE inhibitors, aural stimulation with capsaicin may reduce the incidence of aspiration pneumonia in patients with dysphagia.

Role of the TREK2 potassium channel in cold and warm thermosensation and in pain perception

Two-pore domain background K+ channels (K2p or KCNK) produce hyperpolarizing currents that control cell membrane polarity and neuronal excitability throughout the nervous system. The TREK2 channel as well as the related TREK1 and TRAAK channels are mechanical-, thermal- and lipid-gated channels that share many regulatory properties. TREK2 is one of the major background channels expressed in rodent nociceptive neurons of the dorsal root ganglia that innervate the skin and deep body tissues, but its role in somatosensory perception and nociception has remained poorly understood. We now report that TREK2 is a regulatory channel that controls the perception of non aversive warm, between 40°C and 46°C, and moderate ambient cool temperatures, between 20°C and 25°C, in mice. TREK2 controls the firing activity of peripheral sensory C-fibers in response to changes in temperature. The role of TREK2 in thermosensation is different from that of TREK1 and TRAAK channels; rather, TREK2, TREK1, and TRAAK channels appear to have complementary roles in thermosensation. TREK2 is also involved in mechanical pain perception and in osmotic pain after sensitization by prostaglandin E2. TREK2 is involved in the cold allodynia that characterizes the neuropathy commonly associated with treatments with the anticancer drug oxaliplatin. These results suggest that positive modulation of the TREK2 channel may have beneficial analgesic effects in these neuropathic conditions.

Localization of SSeCKS in unmyelinated primary sensory neurons

BackgroundSSeCKS (Src SupprEssed C Kinase Substrate) is a proposed protein kinase C substrate/A kinase anchoring protein (AKAP) that has recently been characterized in the rat peripheral nervous system. It has been shown that approximately 40% of small primary sensory neurons contain SSeCKS-immunoreactivity in a population largely separate from substance P (95.2%), calcitonin gene related peptide (95.3%), or fluoride resistant acid phosphatase (55.0%) labeled cells. In the spinal cord, it was found that SSeCKS-immunoreactive axon collaterals terminate in the dorsal third of lamina II outer in a region similar to that of unmyelinated C-, or small diameter myelinated Aδ-, fibers. However, the precise characterization of the anatomical profile of the primary sensory neurons containing SSeCKS remains to be determined. Here, immunohistochemical labeling at the light and ultrastructural level is used to clarify the myelination status of SSeCKS-containing sensory neuron axons and to further clarify the morphometric, and provide insight into the functional, classification of SSeCKS-IR sensory neurons.MethodsColocalization studies of SSeCKS with myelination markers, ultrastructural localization of SSeCKS labeling and ablation of largely unmyelinated sensory fibers by neonatal capsaicin administration were all used to establish whether SSeCKS containing sensory neurons represent a subpopulation of unmyelinated primary sensory C-fibers.ResultsDouble labeling studies of SSeCKS with CNPase in the dorsal horn and Pzero in the periphery showed that SSeCKS immunoreactivity was observed predominantly in association with unmyelinated primary sensory fibers. At the ultrastructural level, SSeCKS immunoreactivity was most commonly associated with axonal membrane margins of unmyelinated fibers. In capsaicin treated rats, SSeCKS immunoreactivity was essentially obliterated in the dorsal horn while in dorsal root ganglia quantitative analysis revealed a 43% reduction in the number of SSeCKS-labeled cells. This attenuation is concomitant with a decrease in fluoride-resistant acid phosphatase labeled fibers in the spinal cord dorsal horn and small neuronal somata in sensory ganglia.ConclusionThese results demonstrate that SSeCKS is primarily localized within a distinct subpopulation of small diameter, largely unmyelinated C-fiber primary sensory neurons putatively involved in nociception.

A mouse model of peripheral postischemic dysesthesia: involvement of reperfusion-induced oxidative stress and TRPA1 channel.

Peripheral postischemic dysesthesia was examined behaviorally in mice and we investigated the underlying molecular mechanism with a focus on oxidative stress. Hind-paw ischemia was induced by tight compression of the ankle with a rubber band, and reperfusion was achieved by cutting the rubber tourniquet. We found that reperfusion after ischemia markedly provoked licking of the reperfused hind paw, which was significantly inhibited by systemic administration of the antioxidant N-acetyl-l-cysteine and the transient receptor potential (TRP) A1 channel blocker HC-030031 [2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide]. Postischemic licking was also significantly inhibited by an intraplantar injection of another antioxidant, phenyl-N-tert-butylnitrone. The TRPV1 channel blocker BCTC [N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide] did not inhibit postischemic licking. An intraplantar injection of hydrogen peroxide elicited hind-paw licking, which was inhibited by N-acetyl-l-cysteine, phenyl-N-tert-butylnitrone, and HC-030031. Postischemic licking was not affected by chemical depletion of sensory C-fibers, but it was inhibited by morphine, which has been shown to inhibit the C- and Aδ-fiber-evoked responses of dorsal horn neurons. Interestingly, postischemic licking was not inhibited by gabapentin and pregabalin, which have been shown to inhibit the C-fiber- but not Aδ-fiber-evoked response. The present results suggest that ischemia-reperfusion induces oxidative stress, which activates TRPA1 channels to provoke postischemic licking. It has been suggested that this behavior is mediated by myelinated (probably Aδ-type) afferent fibers. Oxidative stress and TRPA1 channels may be potential targets to treat peripheral ischemia-associated dysesthesia.

Opioid receptor bronchial tree: current science.

Systemic opioids have the evidence to support their use in refractory dyspnea; however, the mechanisms of how they exert their effects are not fully understood. The relevance of peripheral mechanisms, in part, is still questioned, especially as a meta-analysis demonstrated no benefit from nebulized opioids. This might be related to the lack of standardization of the inhalation methods. There is a need to clarify whether peripheral opioid receptors may serve as the target for inhaled treatment and what are the potential peripheral mechanisms of opioids. Opioidergic systems are present in structures important for the regulation of bronchial and pulmonary vascular responses, as well as breathlessness perception in the human respiratory system. Opioid receptors located in the pulmonary neuroendocrine cells (PNECs) and sensory C-fibers within the bronchial epithelium are easily accessible for inhaled treatment. Morphine administrated by a pneumodosimetric method shows a different pharmacokinetic profile to those described for systemic routes, suggesting local metabolism in lung. Research suggests that peripheral opioid receptors in lungs may be utilized as a target for therapeutic interventions. According to this hypothesis, to achieve breathlessness relief, opioids should be administered in close proximity to their receptors in the PNECs and sensory C-fibers of the bronchial epithelium.

TRPV1 inhibition does not prevent cold dry air-elicited symptoms in non-allergic rhinitis

The transient receptor potential vanilloid 1 (TRPV1)-expressing sensory C-fibers may play a role in the development of nasal hyper-responsiveness and symptoms of non-allergic rhinitis (NAR). To evaluate the effects of a TRPV1-antagonist, SB-705498, on cold dry air (CDA)-induced symptoms in patients with NAR. This randomized, double-blind, placebo-controlled, crossover study evaluated 14 days of once daily, topical intranasal SB-705498 12 mg in 40 patients with NAR using a CDA challenge experimental model in an environmental exposure chamber (EEC, Cetero Research, Mississauga, Ontario). The primary endpoint was total symptom score (TSS), expressed as weighted mean over 60 minutes (WM0-60) or maximum TSS at 1 hour and 24 hours postdosing. Treatment with SB-705498, relative to placebo, did not improve WM0-60 or maximum TSS at 1 hour and 24 hours post-dosing on days 1 or 14. Mean (95% CI) treatment differences (SB-705498 - placebo) on day 14 were, for WM0-60 at 1 hour: -0.12 (-0.60, 0.36); for maximum TSS at 1 hour: -0.03 (-0.58, 0.51). SB-705498 had no impact on any other efficacy parameters. SB-705498 was well tolerated and pharmacokinetics analysis supported the dosing regimen. SB-705498 12 mg for 14 days did not alleviate the CDA-induced symptoms of NAR. Despite engagement of the TRPV1 receptor, there was no translation to clinical efficacy, suggesting redundancy in symptom pathways.

Substance P-Saporin for Bone Cancer Pain in Dogs

Substance P-Saporin for Bone Cancer Pain in Dogs

FGF1 and 18 increase TRPV1 and TRPA1 responses in sensory C-fibers

Allergic asthma is an inflammatory disease that is associated with airway hyperreactivity (AHR). AHR is characterized by cough, dyspnea and an enhanced sputum production in response to many environmental stimuli such as cold air, cigarette smoke and ozone. Evidence has been provided that sensory neurons, especially the unmyelinated C-fibers, might contribute to AHR. Airway innervating C-fibers express transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1).

Neurturin expression in a mouse model of allergic asthma and its effects on vagal sensory C-fibers

Neurotrophic factors can alter the functional properties of sensory C-fibers in allergic asthma. Neurturin is a neurotrophic factor in the Glial Cell Line-Derived Neurotrophic Factor (GDNF) family of ligands, binds to its receptor GFRα2 and signals via co-receptor RET. Previously, we were able to demonstrate that some bronchopulmonary vagal C-fibers co-express not only GFRα2 and RET but also transient receptor potential channel vanilloid 1 and ankyrin 1 (TRPV1 and TRPA1). These TRP-channels are activated by many environmental irritants that induce allergic reactions like dyspnea, cough, hypersecretion and bronchoconstriction in patients suffering from allergic asthma.

Relationship of pulmonary function response to ozone exposure and capsaicin cough sensitivity

Context: Challenge studies in humans have shown considerable interindividual variability in pulmonary impairment across ozone exposure.Objective: Since previous results suggested effect modulation by neural mechanism, we investigated sensory C-fiber reactivity in relationship to ozone-triggered response pattern.Methods: Cough reflex thresholds reflecting C-fiber sensitivity were evaluated by capsaicin single breath dose–response method. Capsaicin concentrations triggering, respectively, two and five or more coughs (C2, C5) were recorded. Sixteen healthy subjects were randomly exposed in an intermittent exercise protocol to ozone concentrations of 240 and 40 ppb (sham exposure). Ozone responsiveness was defined by a decrease in forced expiratory volume in 1 s (FEV1) of more than 5%.Results: Based on a dichotomous classification, subjects with enhanced reactivity to ozone had lower cough thresholds than non-responders (C2, p = 0.035; C5, p = 0.086). Over all, we could demonstrate relationships between capsaicin sensitivity and ozone-triggered changes in FEV1, peak expiratory flow and maximal expiratory flow at 50% vital capacity but not in specific airway resistance.Conclusion: Our results suggest that capsaicin challenge tests might be useful to characterize subjects with enhanced pulmonary function response towards inhalant irritants.

Contribution of sensory C-fiber neuron injury to mechanical dynamic allodynia in a murine model of postherpetic neuralgia

Mechanical dynamic allodynia is a hallmark symptom of postherpetic neuralgia, but the mechanisms are unclear. This study examined the participation of injury to sensory C-fiber and A-fiber neurons in postherpetic dynamic allodynia. Percutaneous inoculation of mice with herpes simplex virus type-1 caused zoster-like skin lesions and dynamic allodynia, which persisted after lesion healed. In postherpetic mice, the intensity of dynamic allodynia was positively and negatively correlated with the withdrawal latency of nociceptive response to heat and the intensity of aversive response to capsaicin, respectively. Calcitonin gene-related peptide immunoreactivity (a C-fiber marker) was markedly reduced, but neurofilament 200 immunoreactivity (an A-fiber neuron marker) was unchanged in the scarred skin of postherpetic mice. In the affected dorsal root ganglion of postherpetic mice, peripherin-immunoreactive (a C-fiber neuron marker) neurons reduced significantly, whereas neurofilament 200-immunoreactive neurons did not. These results suggest that postherpetic dynamic allodynia is associated with injury to sensory C-fiber neurons and little damage to A-fiber neurons.

Activation of kinin B1 receptor evokes hyperthermia through a vagal sensory mechanism in the rat

BackgroundKinins are mediators of pain and inflammation. Their role in thermoregulation is, however, unknown despite the fact the B1 receptor (B1R) was found implicated in lipopolysaccharide (LPS)-induced fever. The aim of this study was to investigate the mechanism by which peripheral B1R affects body core temperature in a rat model known to show up-regulated levels of B1R.MethodsMale Sprague–Dawley rats received streptozotocin (STZ, 65 mg/kg; i.p.) to enhance B1R expression. Control rats received the vehicle only. One week later, rectal temperature was measured in awake rats after i.p. injection of increasing doses (0.01 to 5 mg/kg) of des-Arg9-Bradykinin (BK) and Sar-[D-Phe8]des-Arg9-BK (B1R agonists) or BK (B2R agonist). The mechanism of B1R-induced hyperthermia was addressed using specific inhibitors and in rats subjected to subdiaphragmatic vagal nerve ligation. B1R mRNA level was measured by quantitative Real Time-polymerase chain reaction (qRT-PCR) and B1R was localized by confocal microscopy.ResultsB1R agonists (0.1 to 5 mg/kg) showed transient (5- to 30-minute) and dose-dependent increases of rectal temperature (+1.5°C) in STZ-treated rats, but not in control rats. BK caused no effect in STZ and control rats. In STZ-treated rats, B1R agonist-induced hyperthermia was blocked by antagonists/inhibitors of B1R (SSR240612), cyclooxygenase-2 (COX-2) (niflumic acid) and nitric oxide synthase (NOS) (L-NAME), and after vagal nerve ligation. In contrast, COX-1 inhibition (indomethacin) had no effect on B1R agonist-induced hyperthermia. In STZ-treated rats, B1R mRNA was significantly increased in the hypothalamus and the vagus nerve where it was co-localized with calcitonin-gene-related peptide in sensory C-fibers.ConclusionB1R, which is induced in inflammatory diseases, could contribute to hyperthermia through a vagal sensory mechanism involving prostaglandins (via COX-2) and nitric oxide.

Asthmatic cough and airway oxidative stress

The mechanisms of cough in asthma are unclear. Asthma is associated with an oxidative stress. Many reactive oxygen species sensitize or activate sensory C-fibers which are capable to induce cough. It was hypothesized that oxidative stress in the airways might contribute to the cough severity in asthma.Exhaled breath condensate samples were collected in ten healthy and 26 asthmatic subjects. The concentration of 8-isoprostane was measured. In addition, the subjects filled in Leicester Cough Questionnaire and underwent cough provocation tests with dry air hyperpnoea and hypertonic saline, among other measurements.Among the asthmatic subjects, high 8-isoprostane was associated with severe cough response to hyperpnoea (p=0.001), low Leicester Cough Questionnaire values (indicating severe subjective cough, p=0.02), and usage of combination asthma drugs (p=0.03–0.04). However, the 8-isoprostane concentrations did not differ significantly between the healthy and the asthmatic subjects.Airway oxidative stress may be associated with experienced cough severity and measured cough sensitivity in asthma.

Stress, the neuroendocrine system and mast cells: current understanding of their role in psoriasis

Psychological stress can activate the hypothalamic–pituitary–adrenal axis and sensory nerves in the brain and skin, resulting in the release of neuroendocrine and neural mediators such as, corticotropin-releasing hormone, neuropeptides, neurotrophins and α-melanocyte-stimulating hormone. These factors can activate mast cells to release proinflammatory mediators and some of them, for example, histamine, tryptase and nerve growth factor, can stimulate sensory C-fibers. Since corticotropin-releasing hormone, sensory nerves and mast cell numbers are increased in the psoriatic lesion, a feedforward loop can exist potentiating the inflammation. Studies in rats and mice have shown that mast cells are activated during standardized stress through corticotropin-releasing hormone and sensory nerves. Therefore, the role of stress, the neuroendocrine system and mast cells in psoriasis is discussed in this article.

Gustatory rhinitis

This review aims to characterize gustatory rhinitis using recent advances in pathophysiology and novel surgical and medical management strategies. A significant amount of research has recently focused on the role of capsaicin and its receptors (TRPV1 and VR1), which can be found on sensory c-fibers in human nasal mucosa and play a critical role in the development of nasal hyperresponsiveness to environmental factors. Blocking the nasal sensory nerve stimulation (via the use of capsaicin desensitization) or outgoing parasympathetic innervation (via endoscopic Vidian neurectomy) may control nasal hyperresponsiveness and therefore prevent the induction of rhinitis symptoms. Gustatory rhinitis is a conspicuous type of food-associated rhinorrhea, which can occasionally be associated with significant quality-of-life impairment. It results from an abnormal gustatory reflex associated with a hyperactive, nonadrenergic, noncholinergic, or peptidergic neural system. The use of nasal ipratropium bromide may be effective, if avoidance is not possible or successful. We have had excellent results with the use of intranasal capsaicin or endoscopic vidian neurectomy (including removal of 4-5 mm of the nerve between pterygopalatine fossa and the sphenoid floor) in patients with nonallergic rhinitis, and these could potentially be used as a last resort in patients with intractable gustatory rhinitis.

Analgesic, anticonvulsant and antioxidant activities of 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one dihydrochloride in mice

Recently we have shown that 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one dihydrochloride (LPP1) is an antinociceptive and local anesthetic agent in rodents. Below an extended study of the pharmacological activity of LPP1 is described. In vitro LPP1 has no affinity for GABAA, opioidergic μ and serotonergic 5-HT1A receptors. The total antioxidant capacity of LPP1 (1–10mM) measured as ABTS radical cation-scavenging activity showed that LPP1 has dose-dependent antioxidant properties in vitro. Low plasma concentration of this compound detected by means of HPLC method 30min after its intraperitoneal administration suggests a rapid conversion to metabolite(s) which may be responsible for its analgesic and anticonvulsant activities in vivo.In vivo the compound's influence on the electroconvulsive threshold and its activity in the maximal electroshock seizure test (MES) were evaluated. The results demonstrated that LPP1 had an anticonvulsant activity in the MES model (ED50=112mg/kg) and at a dose of 50mg/kg was able to elevate the electroconvulsive threshold for 8mA as compared to the vehicle-treated mice. The analgesic activity of LPP1 was investigated in the acetic acid-induced writhing test in two groups of mice: animals with sensory C-fibers ablated, and mice with C-fibers unimpaired. It proved the potent activity of this compound in both groups (approximately 85% as compared to the vehicle-treated mice). The adverse effects of LPP1 were evaluated as acute toxicity (LD50=747.8mg/kg) and motor coordination impairments in the rotarod and chimney tests. The results from these tests show that LPP1 at doses higher than 100mg/kg is likely to impair the motor performance of experimental animals. Concluding, LPP1 is an analgesic and anticonvulsant compound which has antioxidant properties in vitro. Further studies are necessary to assess whether the antioxidant activity and the receptor profiling demonstrated in vitro can be confirmed for its metabolite(s) that are formed in vivo.

TRPV1: A useful therapeutic target for patients with vulnerable coronary plaques

Acute coronary syndromes are generally caused by atherosclerotic plaque rupture. Inflammation is one of the most important features of vulnerable plaque. Adventitial vanilloid receptor TRPV1 and sensory C-fibers may play a pistol role for adventitial inflammation. TRPV1 is also present in platelets, and the presence of this receptor may provide a link between inflammatory mediators and platelet activation in atherosclerosis. The hypothesis we propose here is that TRPV1 may be a useful therapeutic target for patients with vulnerable coronary plaques.The fact that statins act directly on sensory neurons to decrease expression of proinflammatory neuropeptides, supports our hypothesis as above. However, the mechanisms mediating this potential effect are poorly understood. Future studies are required to determine whether downregulated expression of TRPV1 contributes to these therapeutic actions.

Suppression of ovalbumin-induced allergic diarrhea by diminished intestinal peristalsis in RAMP1-deficient mice

Recent studies have revealed that various neurotransmitters regulate the immune system via their receptors expressed on the immune cells. Calcitonin gene-related peptide (CGRP), a sensory nerve C-fiber neuropeptide, is also known to have the ability to modulate the functions of immune cells in vitro. However, the contribution of CGRP to the immune regulation in vivo remains to be fully elucidated. Here we report that mice deficient in receptor activity-modifying protein 1 (RAMP1), which is a subunit of the CGRP receptor, showed a significantly lower incidence of diarrhea compared with wild-type (WT) mice in the ovalbumin (OVA)-induced food allergic model. Serum OVA-specific IgE levels and the differentiation of T helper cells was comparable in WT mice and RAMP1-deficient mice. Moreover, there were no significant differences between recruitment and degranulation of mast cells in the small intestine of these mice. In contrast, significantly diminished intestinal peristalsis was observed by the allergy induction in RAMP1-deficient mice compared with WT mice. These results suggest that this suppression of allergic diarrhea is due to the diminished intestinal peristalsis in RAMP1-deficient mice.

Proliferation of sensory C-fibers and subsequent neurogenic inflammation in rat airway induced by inhaled lipopolysaccharide

Lipopolysaccharide (LPS) is associated with the development and exacerbation of airway inflammation. Increases in innervation of sensory C-fibers and tachykinin receptors, which mainly involve overproduction of neurotrophins such as nerve growth factor (NGF), may enhance neurogenic inflammation. Expression of NGF and its receptors in rat lungs is known to decline with age. We examined whether inhaled LPS causes proliferation of sensory C-fibers, increased expression of tachykinin receptors and subsequent enhancement of neurogenic inflammation in the airways of preweaning rats. Wistar male rats aged 2 weeks inhaled aerosolized LPS derived from Escherichia coli (0.1mg/ml) for 30min. Evans blue dye leakage into the trachea induced by gaseous formaldehyde or intravenous capsaicin was measured as an index of tachykinin NK1 receptor-mediated vascular permeability. Expression of substance P-immunoreactive nerves, tachykinin NK1 receptors, tumor necrosis factor (TNF)-α and NGF in the trachea was also assessed immunohistochemically. Neurogenic plasma leakage in the trachea increased significantly between 7 and 21 days after LPS inhalation. Expression of TNF-α, NGF, substance P-immunoreactive nerves and tachykinin NK1 receptors was enhanced, peaking at 28h, 7 days, 14 days and 14 days after LPS inhalation, respectively. Pretreatment with infliximab, a blocking antibody for TNF-α, almost completely abolished the airway changes seen after LPS inhalation. In conclusion, inhaled LPS increased innervation of sensory C-fibers and expression of tachykinin NK1 receptors in the airway, probably resulting in enhancement of neurogenic airway inflammation. These airway responses may be caused by overproduction of neurotrophins including NGF, mainly through a TNF-α-mediated pathway.

A role for ATP in the mechanical activation of nodose C‐fibers in guinea pig lungs

Activation of vagal afferent sensory C-fibers in the lungs leads to reflex responses that produce many of the symptoms associated with airway allergy. There are two subtypes of respiratory C-fibers whose cell bodies reside within two distinct ganglia, the nodose and jugular, and whose properties allow for differing responses to stimuli. We here used extracellular recording of action potentials in an ex vivo isolated, perfused lung-nerve preparation to study the electrical activity of nodose C-fibers in response to mechanical stimulati in guinea pig lung. We used smooth muscle agonists to induce bronchoconstriction, thereby producing a mechanical stimulus, and found that treatment with both histamine (HA; 30 μM; n=15) and methacholine (MCh; 10 μM; n=4) caused strong action potential discharge in nodose C-fibers (10 ± 2 Hz and 15 ± 8 Hz respectively), but not in jugular C-fibers (n=8). Responses to HA were significantly reduced (P<0.05) by blockade of smooth muscle contraction with isoproterenol (100 μM), suggesting that a component of the response is mechanical in nature. The HA-induced activation of the nodose C-fibers was blocked by pretreatment the H1 receptor antagonist pyrilamine (1 μM; n=5). As ATP activation of P2X3 receptors has been found to play a role in mechanosensory transduction, we examined the effect of P2X3 receptor inhibition on the mechanical activation of nodose C-fibers and found that pretreatment with the P2X3 receptor antagonist AF353 (100 μM; n=5) blocked the response to HA. These results suggest that ATP released within the tissues in response to rapid smooth muscle contraction may play a role in the mechanical activation of nodose C-fibers.