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      Changes in Levels of Nerve Growth Factor in Nasal Secretions after Capsaicin Inhalation in Patients with Airway Symptoms from Scents and Chemicals

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          Abstract

          Patients complaining of upper and lower airway symptoms caused by scents and chemicals have previously been shown to have increased cough sensitivity to inhaled capsaicin, but the precise mechanisms behind this reaction are unknown. Hypothesizing that a neurochemical alteration related to sensory hyperreactivity (SHR) of the airway mucosa occurs, we measured levels of nerve growth factor (NGF) in nasal lavage fluid (NAL) before and after capsaicin inhalation provocations and related the capsaicin cough sensitivity to the NGF levels. Thirteen patients with SHR and 14 control subjects were provoked with capsaicin inhalation at three different doses. We measured NGF in NAL before and after provocation and recorded cough and capsaicin-induced symptoms. All subjects demonstrated a dose-dependent cough response to capsaicin inhalation, with a more pronounced effect in patients than in controls. Basal levels of NGF were significantly lower in the patient group than in the control subjects ( p < 0.01). After capsaicin provocation, the patients showed a significant increase in NGF ( p < 0.01), which was related to capsaicin cough sensitivity. The findings demonstrate that, in patients with airway symptoms induced by scents and chemicals, SHR is real and measurable, demonstrating a pathophysiology in the airways of these patients compared to healthy subjects.

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          Most cited references35

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          Impaired nociception and pain sensation in mice lacking the capsaicin receptor.

          The capsaicin (vanilloid) receptor VR1 is a cation channel expressed by primary sensory neurons of the "pain" pathway. Heterologously expressed VR1 can be activated by vanilloid compounds, protons, or heat (>43 degrees C), but whether this channel contributes to chemical or thermal sensitivity in vivo is not known. Here, we demonstrate that sensory neurons from mice lacking VR1 are severely deficient in their responses to each of these noxious stimuli. VR1-/- mice showed normal responses to noxious mechanical stimuli but exhibited no vanilloid-evoked pain behavior, were impaired in the detection of painful heat, and showed little thermal hypersensitivity in the setting of inflammation. Thus, VR1 is essential for selective modalities of pain sensation and for tissue injury-induced thermal hyperalgesia.
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            A capsaicin-receptor homologue with a high threshold for noxious heat.

            Pain-producing heat is detected by several classes of nociceptive sensory neuron that differ in their thermal response thresholds. The cloned capsaicin receptor, also known as the vanilloid receptor subtype 1 (VR1), is a heat-gated ion channel that has been proposed to mediate responses of small-diameter sensory neurons to moderate (43 degrees C) thermal stimuli. VR1 is also activated by protons, indicating that it may participate in the detection of noxious thermal and chemical stimuli in vivo. Here we identify a structurally related receptor, VRL-1, that does not respond to capsaicin, acid or moderate heat. Instead, VRL-1 is activated by high temperatures, with a threshold of approximately 52 degrees C. Within sensory ganglia, VRL-1 is most prominently expressed by a subset of medium- to large-diameter neurons, making it a candidate receptor for transducing high-threshold heat responses in this class of cells. VRL-1 transcripts are not restricted to the sensory nervous system, indicating that this channel may be activated by stimuli other than heat. We propose that responses to noxious heat involve these related, but distinct, ion-channel subtypes that together detect a range of stimulus intensities.
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              Nerve growth factor acutely sensitizes the response of adult rat sensory neurons to capsaicin.

              Perforated patch clamp recordings were made from 118 voltage clamped (-60 mV), capsaicin-responsive dorsal root ganglion (DRG) cells (<30 microns) maintained in dissociated cell culture (6-24 h). A second puff of capsaicin 10 min later always evoked a substantially smaller inward current than the initial puff (tachyphylaxis). Bath-application of NGF (2, 10 or 100 ng/ml) during the 10-min interval resulted in facilitation of the second response in a dose dependent manner in 67% of cells studied. NT-4/5 exerted similar effects but NT-3 did not. Ten minute pretreatment with NGF increased the initial response to capsaicin. We conclude that NGF acutely conditions the response to capsaicin via direct action on DRG cells. Since the capsaicin receptor (VR1) mediates noxious heat sensitivity of polymodal nociceptors, acute sensitization of the noxious heat response by NGF and NT-4/5 may involve a direct action on VR1.
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                Author and article information

                Journal
                Environ Health Perspect
                Environmental Health Perspectives
                National Institue of Environmental Health Sciences
                0091-6765
                July 2005
                17 March 2005
                : 113
                : 7
                : 849-852
                Affiliations
                1Asthma and Allergy Research Group, Department of Respiratory Medicine and Allergy, ahlgrenska University Hospital, Göteborg, Sweden
                2Allergy Centre, Central Hospital, Skövde, Sweden
                Author notes
                Address correspondence to E. Millqvist, Asthma and Allergy Research Group, Department of Respiratory Medicine and Allergy, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. Telephone: 46-31-3423635. Fax: 46-31-417824. E-mail: eva.millqvist@medfak.gu.se

                We thank S. Rak for valuable discussions and E. Carlsson for skillful laboratory assistance.

                This study was supported by grants from the Vårdal Foundation, the Regional Health Care Authority of West Sweden, and the Swedish Heart and Lung Foundation.

                The authors declare they have no competing financial interests.

                Article
                ehp0113-000849
                10.1289/ehp.7657
                1257644
                16002371
                5a2df37e-f78d-40d7-8e7d-97dccf59f02b
                This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.
                History
                : 13 October 2004
                : 17 March 2005
                Categories
                Research

                Public health
                sensory hyperreactivity,multiple chemical sensitivity,nerve growth factor,airway symptoms,chemical intolerance,nasal lavage fluid

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