http://www.ncbi.nlm.nih.

gov/pubmed/9883301 Baraniuk 1998

Final Report: Nociceptive Dysfunction and Environmental Exposures EPA Grant Number: R825814 Title: Nociceptive Dysfunction and Environmental Exposures Investigators: Baraniuk, James N. , Chase, Gary , Clauw, Daniel J. , Park, Karen Institution: Georgetown University EPA Project Officer: Saint, Chris Project Period: January 22, 1998 through January 21, 2001 Project Amount: $679,956 RFA: Issues in Human Health Risk Assessment (1997) Research Category: Human Health , Health Effects Description: Objective: The specific objectives of this research project were to demonstrate that: (1) irritant rhinitis (IR) subjects have fibromyalgia/chronic fatigue syndrome (FM/CFS) and regional pain syndromes; (2) IR and FM/CFS subjects have significant nasal nociceptive nerve dysfunction compared to normal (N) and allergic rhinitis (AR); and (3) IR subjects have cutaneous nociceptive dysfunction. Exposure to low levels of cigarette smoke and other volatile substances leads to excessive, local, systemic, and central nervous system symptoms. We proposed that the health effects of presumed environmental irritants are more related to the degree of underlying nociceptive nerve dysfunction than to the nature of the environmental agent itself. We proposed that these environmental irritation syndromes overlap with FM/CFS. FM/CFS is characterized by fatigue, autonomic, neuroendocrine, neurocognitive dysfunction, and local and generalized pain and tenderness. Summary/Accomplishments (Outputs/Outcomes): During our investigation we made several significant discoveries. Tobacco sensitivity was defined by a newly validated questionnaire. Tobacco sensitivity was assessed in a group known to have multiple systemic complaints (CFS, n= 141) and (N, n= 154). The prevalence of tobacco sensitivity was 51 percent in CFS, and 28 percent in normal, non-CFS subjects. Tobacco sensitivity was correlated with other syndromes such as IR, fatigue, irritable bowel syndrome (IBS), irritable bladder, generalized musculoskeletal complaints, neurocognitive dysfunction, sleep irregularities, otolaryngological complaints (including chronic sinusitis), and a higher number of perceived upper respiratory tract infections per year. IR is a superior term used to describe noninflammatory rhinitis syndromes that previously have been termed "vasomotor rhinitis." Tobacco sensitivity strongly was correlated with IR, humidity, and general weather changes.

 Rhinitis scores, another questionnaire based on measures that was validated as part of this study, significantly was elevated in tobacco sensitive subjects in both CFS and normal groups. There also was a strong association with magnetite-coated sand (MCS). Tobacco sensitive subjects had high scores for symptoms induced in all body systems by chemicals such as volatile organic compounds (VOC) and fine particulate material (FPM). The high concordances of tobacco sensitivity with syndromes such as IR, MCS, and IBS present several potential, generalized defects. On the afferent sensory side, these subjects may share high sensitivity (low threshold for stimulation) of specific afferent nerve subpopulations that respond to VOCs and FPM. Dysfunction of spinal cord sensation gating mechanisms, brain stem integration, and higher central nervous system perceptual centers may lead to prolonged or intensified perceptions of irritation, prolonged sensation without neural accommodation to the stimulus, or recurrent pain mechanisms reminiscent of chronic pain syndromes such as "phantom limb" pain. Local responses in airway mucosal or skin surfaces may be related to neural or other sentinel cell sensitivity to these agents. Direct stimulation of nociceptive nerves in airway mucosa or skin may stimulate axon responses that lead to the peripheral manifestations of the reaction, plus the central perception of irritation or other sensations. Direct toxic effects on multiple organ systems due to toxin absorption seems less likely. A more likely effect or system is brain stem autonomic reflexes causing systemic responses in multiple organs. In turn, effects such as peristalsis or tachycardia may stimulate visceral sensory neurons that lead to their own dysesthetic visceral sensations. Tobacco sensitivity, MCS, CFS, IBS, and related syndromes are caused by exaggerated irritation sensations that are the result of dysfunction of specific subsets of afferent Type C or A neurons or their central nervous system relay pathways. Objective 1. To Demonstrate That IR Subjects Have FM/CFS and Regional Pain Syndromes. Our first objective was to determine the prevalence of elevated smoke scores, an indicator of IR, in nonselected N, AR, and FM/CFS populations. A Tobacco Score questionnaire was developed to identify and characterize subjects with this sensitivity. The Tobacco Score was positive in 16 percent of control and 51 percent of CFS subjects. Significant correlations were found between Tobacco Score, IR Score, and history of sinusitis. Intermediate relationships were found with history of AR, Systemic Complaints Score, and MCS. Factors having no influence included gender, the severity of CFS symptoms, pain thresholds, and allergy skin tests. Based on these results, we concluded that tobacco sensitivity was correlated with measures of upper airway irritation and nonallergic sensitivity to triggers such as weather changes. The spectrum of symptoms, high prevalence in CFS, and absence of a relationship to atopy suggest that these nonallergic irritant syndromes may share a common neuropathophysiology. We also attempted to determine the number of IR subjects who have FM and/or CFS. Based on FM prevalence, it is estimated that 2 AR and 2 N subjects (10 percent) will meet FM or CFS criteria (Clauw, 1995). If 9 out of 20 IR subjects meet FM or CFS criteria, chi (Wolfe, Smythe, Yunus, et al., 1990) will give p = 0.03 and a power of 90 percent, indicating the rate of FM/CFS is higher in IR than N. If 12 out of 20 IR subjects meet FM or CFS criteria, the rates in IR and FM/CFS groups will not significantly be different. Equivocal results may require an increase in sample size that would be based upon a power of 90 percent (p <0.05). Irritation symptoms after exposure to "nonspecific" stimuli are often attributed to non AR (vasomotor rhinitis). This is a heterogeneous syndrome of exclusion based on nasal symptoms with negative allergy skin tests. IR was present in 11 percent of control and 47 percent of CFS subjects. In multivariate analysis, a positive IR score was correlated with a history of rhinitis complaints, systemic complaints such as fatigue, sensations of congestion, rhinorrhea induced by meteorological conditions, tobacco smoke, odors, perfumes, other volatile materials, and diagnoses of CFS and MCS. Although atopy was not correlated to IR, 51 percent of AR subjects had a positive IR score. The IR score defined a population with irritant-induced nasal congestion and rhinorrhea who also had significant systemic complaints. Similar neural mechanisms may underlie the spectrum of IR, CFS, and MCS.

Objective 2. To Demonstrate That IR and FM/CFS Subjects Have Significant Nasal Nociceptive Nerve Dysfunction Compared to N and AR Subjects. In the nose (Littlejohn, Weinstein, Helme, 1987), hypertonic saline (HTS) (Holzer, 1991) stimulates nociceptive sensory nerves, and recruits parasympathetic reflexes (Park, Max, Robinovitz, Gracely, Bennett, 1995). Duration of pain, IgG, and 7F10-mucin secretion are disordered in FM/CFS compared to N and AR control subjects. IR subjects were anticipated to have similar dysfunction. This aim precisely will define nociceptive nerve, central nervous system (CNS), and parasympathetic reflex pathology in IR and FM/CFS. Dysfunction of nociceptive nerve axon responses may be identified. To determine if IR subjects have increased pain duration, pain intensity, drip and block scores relative to N subjects after HTS nasal provocation, we statistically analyzed the linear analog scale data. The effects of hypertonic saline nasal provocation are still under statistical analysis. Therefore, it is premature to make conclusions about the data. IR, FM/CFS, AR, and N subjects (n= 20 per group) will return for HTS provocation with acoustic rhinometry. The volume air in each nasal cavity can be measured by a SONAR-like device (Eccovision) that bounces sound waves off the interior mucosal surfaces of the nose, detects the reflections, and estimates the cavity cross-sectional area as a function of distance from the nasal opening (Fukuda Strauss, Hickie, Sharpe, Dobbins, Komaroff, et al., 1994). The aIR scorepace volume in the IL and CL nasal cavities were measured 5 minutes after each HTS application. Incremental decreases in nasal volumes will suggest increases in mucosal thickening (and volume). Changes due to direct axon response, and reflex effects were detected on the IL side, while the CL side showed cholinergic and noncholinergic vasodilator effects. IR and CFS subjects may significantly have greater decreases in the volumes of air in their IL nasal cavities compared to N subjects. Significant increases in blockage with no change in nasal cavity volumes may occur in IR (and FM/CFS), and would suggest a disconnect between nociceptive nerve activation, CNS function (perception of mucosal sensations), and actual mucosal events (mucosal thickening, an IR score pace volume, nasal airway resistance). This was analogous to IBS (Joos, Germonpre, Pauwels, 1995; Chrousos, Gold, 1992). HTS nasal provocations did not cause significant changes in acoustic rhinometry results in normal, CFS, or IR populations. Small decreases in aIR scorepace volumes were correlated with the amount of glandular secretions produced. Therefore, stimulation of the hypertonic sensitive-mechanisms, including the nociceptive nerve axon response, led to glandular secretion without vascular responses (either plasma extravasation or deep venous sinusoid dilation with nasal obstruction). Glandular mucus secretion appeared to be responsible for the changes in acoustic rhinometry results. In some series, the acoustic rhinometry actually increased with hypertonic saline provocations. This suggests that perception of nasal mucus is one factor used to assess nasal patency. Alterations in this nociceptive nerve sensory function could lead to misinterpretation of normal airflow as a blocked, full, or congested nasal passage or "sinus" headache. To determine if IR subjects have disordered secretory responses after HTS provocation, nasal mucus components were collected, measured, and statistical differences between groups were assessed as described above. IR and FM/CFS subjects were anticipated to have very similar results that significantly differ from N and AR groups. IR subjects are anticipated to have longer pain duration, dysfunctional IL vascular permeability (IgG), and CL parasympathetic reflexes (7F10mucin). Glandular secretion in IR were compared on the IL and CL sides to determine if there are changes in cholinergic reflex effects. An increase in IL secretion (compared to N) with no significant change on the CL side (as found in CFS), would suggest enhanced direct mechanisms, including nociceptive nerve axon responses with neurogenic inflammation, and direct activation of epithelial cells (Holzer P, 1991). Future investigations are envisioned to examine the ability of substance P (SP) antagonists to reduce the IL glandular secretion. Determine if Nociceptive Nerve Axon Responses Have Been Activated by Measuring Neuropeptide Release in vivo. We measured substance P (Tomkinson, Eccles, 1996) and calcitonin gene related peptide (CGRP) levels in IL nasal secretions to determine if there are changes in neuropeptide release under baseline conditions, and after 24 x NS (Ali, Yuta, Baraniuk, submitted 1997).

Vasoactive intestinal polypeptide (VIP) (parasympathetic) and neuropeptide Y NPY (sympathetic) neurotransmitter levels were measured as control peptides (Taddese, Nah, McCleskey, 1995). SP and CGRP measurements were made. Nasal secretions were collected in the usual fashion at baseline and after HTS, 400 KIU/ml aprotinin, and 1 mM EDTA added and samples frozen. Peptides were separated on C18 Sep-Pak cartridges, then measured by radioimmunoassay (RIA, Peninsula, Belmont, CA). These assays are in constant use in our laboratory for our FM, CFS, and Persian Gulf Syndrome investigations. We anticipated IR and FM/CFS subjects would have: (a) lower baseline SP and CGRP levels indicating continuous release with depletion or neural dysfunction, (b) dose response increases in SP and CGRP release, or (c) higher maximal SP and CGRP release after 24 x NS indicating enhanced neurogenic inflammation. CGRP significantly was higher at baseline (normal saline lavage) in CFS (n= 7) than normal control subjects (n= 22) (p= 0.0495). CGRP marginally increased with increasing strength of hypertonic saline provocation doses in normal subjects, but not with the CFS group. The CFS group had a high prevalence of tobacco sensitivity. Substance P was found to degrade very rapidly in nasal secretion peptidases. Very low concentrations were detected and showed no significant changes from baseline or between groups. VIP and NPY. Previous findings suggest VIP will be released on IL and CL sides. However, no changes in NPY are anticipated. NPY will be a reference peptide in this system.

Figure 1. CGRP and NPY Tonicity Neuropeptide Y (NPY). Very unexpectedly, NPY, a marker of sympathetic nerve discharge, significantly was higher in CFS subjects than normal controls. The hypertonic saline dose responses

were roughly parallel, so that significant differences (p <0.05) were found between the 2 groups at 1 x NS, 6 x NS, and 24 x NS. NPY was expected to be lower in CFS and consistent with sympathetic hypofunction. However, elevated levels at baseline and with provocation suggest that NPY may be chronically released (or not metabolized or cleared from the system) in CFS. Given the known sympathetic hypofunction in CFS (e.g., neural hypotension), these results suggest that there is elevated sympathetic neuropeptide release, but that it is not effective. In turn, this suggests dysfunction at the level of the vasoconstricting NPY (or adrenergic) receptors or an intraarterialsmooth muscle contraction deficit. This hypotheses requires additional preliminary neuropeptide measurements to confirm these results, and a different study design to identify a loss of vasoconstrictor tone. We have collected data on oxymetazoline ("Afrin")-induced vasoconstriction in the noses of these subjects, and will be assessing these catecholaminergic responses to see if there is less constriction in CFS than normal subjects. In preliminary data, there appear to be no baseline differences between normal and CFS subjects, while AR subjects show clear reductions in their free nasal aIR scorepace volume. The VIP also gave unexpected results. The small numbers of CFS subjects tested meant that no significant differences were found between normal groups and CFS groups. However, the differences at baseline (1 x NS) are anticipated to become significant as more subjects are tested. The large and very significant increase in VIP (mean-SEM) after 3 x NS in the normal group is difficult to explain. These points could be dismissed as outliers but the standard error was very small for these 12 provocations. This discharge occurs at a time point when there is little pain, and therefore, minimal stimuli for a parasympathetic release of this neuropeptide. An alternative may be the release of VIP from a non-neural source by the IR scoret significant hypertonic stimulus, with rapid depletion or tachyphylaxis of this response.

Figure 2. VIP Tonicity Neuropeptide Conclusions. Overall, the most outstanding differences in neuropeptides were the significantly higher NPY and CGRP levels at baseline in CFS subjects, the consistently higher NPY levels after each HTS dose in CFS, and the trend to lower baseline VIP levels in CFS subjects. Measure Levels of The Neurotrophic Cytokines IL-8 and Nerve Growth Factor (NGF). IL-8 is measured by novel double-capture ELISA in collaboration with CytImmune Sciences (College Park, MD). NGF is measured by ELISA (Boehringer Mannheim, Indianapolis, IN). IL-8 and NGF levels may significantly be higher in IR and FM/CFS secretions at baseline and after 24 x NS compared to N. We now have run out of nasal lavage fluid and can not perform the IL-8 assays as planned. Nerve growth factor assays were totally unreliable and we have stopped doing them.

Determination if HTS Neurogenic Inflammation Induces Neutrophil or Eosinophil Influx. ECP and Elastase. Subjects had an additional secretion collection after 4 hours to measure ECP (Kabi Pharma, Uppsala, Sweden) and neutrophil elastase (ELISAs). (ECP and elastase levels were more reliable and sensitive than changes in cell numbers.) No differences were anticipated at baseline for IR, FM/CFS, and N subjects. However, neurogenic inflammation may induce immediate or delayed (4 hour) neutrophil and eosinophil infiltration. We proposed that HTS would induce delayed infiltration in IR, FM/CFS, and AR subjects, implicating neurogenic inflammation and leukocyte infiltration in these disorders. Neutrophil Elastase. We initiated our studies by measuring elastase in baseline nasal secretions from FM/CFS subjects who have a high prevalence of tobacco sensitivity. Myeloperoxidase (MPO). More recently, we have assessed lavage fluid neutrophilia by MPO ELISA. Negative control subjects who did not have AR or sinusitis showed significant decreases in MPO levels during fluticasone treatment. This suggests that their recruitment by factors such as epithelial IL-8 or endothelial adhesion molecules may be down regulated. Similar changes were not found in AR or sinusitis. MPO remained unchanged by statistical measures, although there was a trend towards lower concentrations. However, the data had wide standard deviations suggesting a wide range of random results, two separate or bipolar responses that were grouped into one group, or the effects of a limited number of exceptionally high or low outliers on the mean data. These currently are under examination. Tobacco sensitivity may have contributed to the wide standard deviations in the AR and sinusitis data. We hypothesized that the tobacco sensitive group had less of a change than those without tobacco sensitivity. This hypothesis is being separately addressed. The delay in generating this analysis is due to the time we have taken to enter all of our data from several similar studies into a locked and secured Excel database. This effort will make post-hoc hypothesis testing by statistical analysis using SAS much more simple and rapid. Objective 3. To Demonstrate That IR Subjects Have Cutaneous Nociceptive Dysfunction. Capsaicin Skin Tests. The back was cleaned with ethanol, and 6 mm Whatman filter paper discs arranged at 10 cm intervals beginning 5 cm to left of the T2 vertebrae, and 5 cm to the right of the midline at T5 (mid-scapula) (Chester, 1993). Diluent (10 l; 70 percent ethanol) was applied to the fIR scoret disc, and sensory testing performed. Then 6.4 mg/ml capsaicin was applied to the fIR scoret right disc, followed by random application of 0.2, 0.4, 0.8, 1.6, and 3.2 mg/ml to the others. All will be immediately covered with paper tape to reduce evaporation. Exactly 30 minutes later, the tape and discs were removed, and the area of erythema traced onto clear acetate sheets. The longest diameter and its orthogonal diameter was measured and added to give the "Sum of Erythema." Pain will be assessed every 5 minutes by 10 cm linear analog scales for the duration of the sensation. Allodynia, or mechanical hyperalgesia, is detected as a change from light touch to unpleasant pain sensation when sweeping a cotton gauze pad at 1 cm/sec from the shoulder towards the 0 and 6.4 mg/ml application sites (Bascom, Fitzgerald, Hudgins, in preparation). This was repeated as 8 radial strokes. Pressure Hyperalgesia was measured by pressing calibrated von Frey fibers (Semmes-Weinstein monofilaments, 1.65 to 6.65 g, Stoelting, Wood Dale, IL) at points 2.5 cm from the 0 and 6.4 mg/ml sites. Subjects will grade sensations on 10 cm linear analog scales, and differences between the two sites determined. Dolorimetry for pressure hyperalgesia then will be assessed at the application sites.62 Pinprick Hyperalgesia, and the area with this change, similarly will/be assessed by dimpling the skin with a sharp safety pin (Bascom, Fitzgerald, Hudgins, in preparation). The area of dysregulated sensation around the 0 and 6.4 mg/ml sites were determined. Capsaicin Dose Responses. Linear relationships were obtained when the log of erythema was plotted versus the log of capsaicin concentration (r2 typically > 0.9). The y-intercept (1 mg/ml capsaicin), and threshold dose generating erythema of 14 mm (1 mm larger than discs) was determined by interpolation of linear regression lines of individual sets of log-log transformed data (Epistat, Richardson, Texas). The y-intercept compares responses at one capsaicin concentration.

The threshold dose compares the relative amount of capsaicin required to initiate nociceptive nerve depolarization. The geometric means for each parameter and for each group was compared. Allodynia. The area of mechanical hyperalgesia was calculated from the average distance of unpleasant sensation from the application site (r) and area = r2. Areas were compared by ANOVA. Pinprick Hyperalgesia. The area with this change was similarly assessed for the 0 and 6.4 mg/ml sites. Pressure Hyperalgesia. Pain sensations were plotted versus calibrated fiber pressure. Capsaicin was anticipated to shift these curves to the left indicating greater pain responses. It was anticipated that these shifts were greater in IR and FM/CFS subjects than N subjects. This study deferred because of delays in finalizing Institutional Review Board and General Clinical Research Center consent. The majority of subjects had already completed their nasal and questionnaire testing once the capsaicin study had been approved. Subtypes of Type C Nociceptive Nerve Fibers and Their Specific Sensations. We reevaluated this plan because a number of new, separate, independent nociceptive nerve populations have been demonstrated. Type C, nonmyelinated nociceptive neurons express capsaicin receptors (vanilloid receptor 1, VR1) that responds to capsaicin, acid pH, and moderate temperature (> 43C). One population uses neuropeptides such as substance P, CGRP as neurotransmitters. The second major population was identified by immunohistochemistry for the IB-4 lectin. The neurotransmitters of these cells have not been identified. A third population mediates itch. These are very narrow, very slow conducting fibers that express histamine H1 receptors (H1-R) and cause large cutaneous flare reactions. CGRP is the major mediator released in the skin by the axon response mechanism and centrally in spinal cord dorsal horn areas that are distinct from pain association neurons. Itch sensations were transmitted from the dorsal horn to the opposite lateral spinothalamic tract, where they terminate on a separate population of thalamic itch relay neurons. The subsequent radiation to suprathalamic nuclei probably also is different than pain stimuli. The cold sensation receptor has been cloned and is the (L)(-) menthol receptor on A nerve fibers. Airflow in the nose leads to evaporation of water from the epithelial lining fluid. Evaporation means that the higher energy water molecules escape into the passing air stream, leaving a relatively lower energy set of molecules in the liquid phase. Temperature is a function of energy. Therefore, air flow induced evaporation reduces the temperature of the nasal mucosal airway epithelial lining fluid. This rapid and transient change in temperature is thought to stimulate the (L)(-) menthol receptors on moderately rapidly conducting Ad nerve fibers that synapse in the brain stem in respiratory centers. This nasal airflow monitor may contribute to sensations of respiratory dyspnea or air hunger, and help determine the brainstem-induced breath-to-breath systemic muscular and other responses that signal depth of respiration, tidal volume, and work of breathing. In a congested nose with no airflow, there will be no cooling, and deep inspiration oral breathing will result. Treatment with rapidly flowing dry air (e.g., nasal prongs in chronic obstructive pulmonary disease (COPD) patients) or application of (L)(-) menthol gives subjects a sensation of improved airflow and decreases their work of breathing. There is no change in nasal airflow resistance (nasal rhinomanometry, nasal inspiratory flow, nasal flow-volume loops) or volume of the nasal IR score pace (acoustic rhinometry). Thus, the sensation of nasal blockage and the mechanisms regulating nasal airflow are disconnected. This is typical of nonAR (see IR above). Since this mechanism may have direct application to tobacco sensitivity sensations, we have redesigned experiments to evaluate (L)(-) menthol sensitivity and the relationship to tobacco-induced sensations. References: Clauw DJ. The pathogenesis of chronic pain and fatigue syndromes, with special reference to fibromyalgia. Medical Hypotheses 1995;44:369-378.

Wolfe F, et al. Criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. The American College of Rheumatology. Arthritis Rheum 1990;33:160-172. Fukuda K, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Annals of Internal Medicine 1994;21:953-959. Schuelderberg A, et al. Chronic fatigue syndrome research: definition and medical outcome assessment. Annals of Internal Medicine 1992;117:326. Manu P, Lane TJ, Matthews DA. The pathophysiology of chronic fatigue syndrome; confirmations, contradictions, and conjectures. International Journal of Psychiatry in Medicine 1992;22:397-408. Gaumond E, Radulovic D, Wethington S, Wilson B, Clauw D, Baraniuk JN. Chronic nonallergic rhinitis complaints identified in chronic fatigue syndrome (CFS). Journal of Allergy and Clinical Immunology 1996;97(2):438. Cleveland CH, Fisher RH, Brestel EP, Esinhard JD, Metzger WJ. Chronic rhinitis: an unrecognized association with fibromyalgia. Allergy Proceedings 1992;13:263-267. Steinberg P, McNutt BE, Marshall P, Schenck C, Lurie N, Pheley A, Peterson PK. Double-blind placebo-controlled study of efficacy of oral terfenadine in the treatment of chronic fatigue syndrome. Journal of Allergy and Clinical Immunology 1996;97(1):119-126. Ali M, Gaumond E, Yuta A, Clauw D, Baraniuk JN. Nonallergic rhinitis (NAR) of chronic fatigue syndrome (CFS). Journal of Allergy and Clinical Immunology 1997;99(6-1):S420. Clauw DJ, Schmidt M, Radulovic D, Slotkoff A, Singer A, Bressette J. The relationship between fibromyalgia and interstitial cystitis. Arthritis and Rheumatism 1994;37:1118. (abstract) Anderson SD, Rodwell LT, Daviskas E, Spring JF, du Toit J. The protective effect of nedocromil sodium and other drugs on airway narrowing provoked by hyperosmolar stimuli: a role for the airway epithelium? Journal of Allergy and Clinical Immunology 1996;98(5-2):S124-S134. Krayenbuhl MC, Hudsith BN, Scadding GK, Brostoff J. Nasal response to allergen and hyperosmolar challenge. Journal of Allergy and Clinical Immunology 1988;18:57-64. Yuta A, Ali M, Baraniuk JN. Hypertonic saline (HTS): comparison of nasal secretion in normal and atopy subjects. American Journal of Respiratory and Critical Care Medicine 1997 (abstract submitted). Ali M, Yuta A, Baraniuk JN. A comparison of nasal symptoms in normal and atopy subjects using a hypertonic saline (HTS) provocation. American Journal of Respiratory and Critical Care Medicine 1997 (abstract submitted). Holzer P. Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacological Reviews and Communications 1991;43:143-201. Littlejohn GO, Weinstein C, Helme RD. Increased neurogenic inflammation in fibrositis syndrome. Journal of Rheumatism 1987;14:1022-1025. Park KM, Max MB, Robinovitz E, Gracely RH, Bennett GJ. Effects of intravenous ketamine, alfentanil, or placebo on pain, pinprick hyperalgesia, and allodynia produced by intradermal capsaicin in human subjects. Pain Reviews 1995;63:163-172.

Bascom R, Kulle T, Kagey-Sobotka A, Proud D. Upper respiratory tract environmental tobacco smoke sensitivity. American Review of Respiratory Disease 1991;143:1304-1311. Willes S, Fitzgerald T, Bascom R. Nasal inhalation challenge studies with sidestream tobacco smoke. Archives of Environmental Health 1992;47:223-230. Bascom R. The upper respiratory tract: mucous membrane irritation. Environmental Health Perspective 1991;95(1):39-44. Bascom R, Fitzgerald TK, Hudgins JL. Effects of intranasal substance P in subjects with and without tobacco smoke sensitivity (in preparation, 2002). Chester AC. Hypothesis: the nasal fatigue reflex. Integrative Physiological Behavior Science 1993;28:76-83. Simon GE, Daniell W, Stockbridge H, Claypoole K, Rosenstock L. Immunolgic, psychological, and neuropsychological factors in multiple chemical sensitivity. Annals of Internal Medicine 1993;119:97-103. Wasserfallen JB, Gold K, Schulman KA, Baraniuk JN. Development and validation of a rhinitis and asthma symptom score for use as an outcome measure in clinical trials. American Journal of Respiratory and Critical Care Medicine 1996;153:A97. Wasserfallen JB, Baraniuk JN, Milzman D, Wethington S, Wilson B, Schulman KA. Asthma symptoms, treatment and cost after an emergency room visit (ERV). Journal of Allergy and Clinical Immunology 1995;95:227. Wasserfallen JB, Gold K, Schulman KA, Milzman D, Baraniuk JN. Development and validation of a rhinoconjunctivitis and asthma symptom score. Journal of Allergy and Clinical Immunology 1997 (in press). Wasserfallen JB. Development and validation of a rhinoconjunctivitis and asthma symptom score. M.S. Thesis. Georgetown University, Health Policy, 1996. Hua XY. Tachykinins and calcitonin gene related peptide in relation to peripheral functions of capsaicin sensitive sensory neurons. Acta Physiologica Scandinavia Supplement 1986;127(551):145. Baraniuk JN, Kowalski M, Kaliner M. Neuropeptides in the skin. In: Bos JB, ed. Skin Immune System (SIS). CRC Press, Baton Rouge, LA, 1990, pp. 307-326. Dray A, Urban L, Dickenson A. Pharmacology of chronic pain. TiPS 1994;15:190-197. Gracely RH, Barcellos SA, Saltzman SJ, Byas-Smith MG, Max MB, Bennett GJ. A mechano-allodynia and cold hyperalgesia following large doses of intradermal capsaicin. Journal of Social Neruoscience 1993;19:1073 (abstract). Torebjork HE, Lundberg LER, LaMotte RH. Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. Journal of Physiology 1992;448(1):765780. Simone DA, Baumann TK, LaMotte RH. Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin. Pain Reviews 1989;38:99-107.

Greenspan JD, McGillis SLB. Stimulus features relevant to the perception of sharpness and mechanically evoked cutaneous pain. Somatosens Mot Res 1991;8:137-147. Raphael GD, Meredith SD, Baraniuk JN, Kaliner M. Nasal reflexes. American Journal of Rhinology 1988;2:8-12. Raphael GR, Baraniuk JN, Kaliner MA. How and why the nose runs. Journal of Allergy and Clinical Immunology 1991;87:457-467. Baraniuk JN. Neural control of human nasal secretion. Pulmonary Pharmacology 1991;4:20-31. Mygind N, Naclerio RM, eds. Allergic and Nonallergic Rhinitis. Philadelphia, PA, 1993. Settipane RA, Settipane GA. Nonallergic rhinitis. Journal of Allergy and Clinical Immunology 1996;16:49-60. Joos GF, Germonpre PR, Pauwels RA. Neurogenic inflammation in human airways: is it important? Thorax 1995;50:217-219. McDonald DM. Neurogenic inflammation in the rat trachea. Changes in venules, leukocytes and epithelial cells. Journal of Neurocytology 1988;17:605-628. Piedemonte G, McDonald DM, Nadel JA. Glucocorticoids inhibit neurogenic plasma extravasation and prevent virus-potentiated extravasation in the rat trachea. Journal of Clinical Investigation 1990;86:1409-1415. Fajac I, Braunstein G, Ickovic MR, Lacronique J, Frossard N. Selective recruitment of eosinophils by substance P after repeated allergen exposure in AR. Allergy 1995;50:970-975. Stjarne P, Lundblad L, Lundberg JM, Anggard A. Capsaicin and nicotine sensitive afferent neurones and nasal secretion in healthy human volunteers and in patients with vasomotor rhinitis. British Journal of Pharmacology 1989;96(3):693-701. Stjarne P, Lacroix JS, Anggard A, Lundberg JM. Compartment analysis of vascular effects of neuropeptides and capsaicin in the pig nasal mucosa. Acta Physiologica Scandinavia 1991;141:335342. Braunstein G, Fajac I, Lacronique J, Frossard N. Clinical and inflammatory responses to exogenous tachykinins in AR. American Review of Respiratory Diseases 1991;144:630-636. Svensson C, Andersson M, Greiff L, Alkner U, Persson CGA. Exudative hyperresponsiveness of the airway microcirculation in seasonal allergic rhinitis. Clinical Exposure Allergy 1995;25:942-950. Riberio-da-Silva A, Kenigsberg RL, Cuello AC. Light and electron microscopic distribution of nerve growth factor receptor-like immunoreactivity in the skin of the rat lower lip. Neuroscience 1991;43:631-646. Lewin G, Mendell LM. Nerve growth factor. Trends in Neuroscience 1993;16:353-359. Barnes PJ. Modulation of neurotransmission in airways. Physiology Review 1992;72:699. Taddese A, Nah SY, McCleskey EW. Selective opioid inhibition of small nociceptive neurons. Science 1995;270(11-24):1366-1369.

Baraniuk JN. Neuropeptide pharmacology. In: Townley RG, Agarwal DK, eds. Immunopharmacology of the Respiratory Tract: Clinical Allergy and Immunology. 1996, pp. 575-603. Kurian SS, Blank MA, Sheppard MN. Vasoactive intestinal polypeptide (VIP) in vasomotor rhinitis. Clinical Biochemistry 1983;11:425-427. Wilde AD, Cook JA, Jones AS. The nasal response to isometric exercise in non-eosinophilic intrinsic rhinitis. Journal of Clinical Otolaryngol 1996;21:84-86. Sternberg EM. Hyperimmune fatigue syndromes: diseases of the stress response? Journal of Rheumatology 1993;20(3):418?421. Griep EN, Boersma JW, de Kloet ER. Altered reactivity of the hypothalamic-pituitary-adrenal axis in the primary fibromyalgia syndrome. Journal of Rheumatology 1993;20:469?474. Crofford LJ, et al. Hypothalamic-pituitary-adrenal axis perturbations in patients with fibromyalgia. Arthritis Rheumatology 1994;37(11):1583?1592. Chourousos GP, Gold PW. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. Journal of the American Medical Association 1992;267:1244-1252. Clauw DJ, et al. Heart rate variability as a measure of autonomic dysfunction in fibromyalgia and chronic fatigue syndrome. Arthritis Rheumatology 1995;38:R25 (abstract). Clauw DJ, et al. Tilt table testing in fibromyalgia. Arthritis Rheumatology 1996;39:R20. (abstract) Mayer EA, Raybould HE. Role of visceral afferent mechanisms in functional bowel disorders. Gastroenterology 1990;99(6):1688?1704. Buzzi M, Bonamini M, Cerbo R. The anatomy and biochemistry of headache. Functional Neurology 1993;8(6):395-402. Lynn R, Friedman L. Irritable bowel syndrome. New England Journal of Medicine 1993;329(1223):1940-1945. Aggarwal A, et al. Predominant symptoms in irritable bowel syndrome correlate with specific autonomic nervous system abnormalities. Gastroenterology 1994;106:945-950. Baraniuk JN. Pathogenesis of allergic rhinitis. Journal of Allergy and Clinical Immunology 1997 (in press). Naclerio RM. Allergy rhinitis. New England Journal of Medicine 1991;325(9-19):860-869. Gergen PJ, Turkeltaub PC, Kovar MG. The prevalence of allergic skin test reactivity to eight common aeroallergens in the U.S. population: results from the second National Health and Nutrition Examination Survey. Journal of Allergy and Clinical Immunology 1987;80:669. Wolfe F, Ross K, Anderson J, Russell IJ. Aspects of fibromyalgia in the general population: sex, pain threshold, and fibromyalgia symptoms. Journal of Rheumatology 1995;22:151-156. Raphael GD, Druce HM, Baraniuk JN, Kaliner MA. Pathophysiology of rhinitis. I. Assessment of the sources of protein in methacholine-induced nasal secretions. American Review of Respiratory Diseases 1988;138:413-420.

Raphael GD, Meredith SD, Baraniuk JN, Druce HM, Banks SM, Kaliner MA. Pathophysiology of rhinitis. II. Assessment of the sources of protein in histamine-induced nasal secretions. American Review of Respiratory Diseases 1989;139:791-800. Raphael GD, Igarashi Y, White MV, Kaliner MA. Pathophysiology of rhinitis. V. Sources of protein in allergen-induced nasal secretions. Journal of Allergy and Clinical Immunology 1991;88:33-43. Raphael GD, Haupstein-Raphael M, Kaliner MA. Gustatory rhinitis: a syndrome of food-induced rhinorrhea. Journal of Allergy and Clinical Immunology 1989;83:110-115. Baraniuk JN, Lundgren JD, Okayama M, Goff J, Mullol J, Merida M, Shelhamer JH, Kaliner MA. Substance P and neurokinin A (NKA) in human nasal mucosa. American Journal of Respiratory Cell and Molecular Biology 1991;4:228-236. Baraniuk JN, Lundgren JD, Goff J, Mullol J, Castellino S, Merida M, Shelhamer JH, Kaliner M. Calcitonin gene related peptide (CGRP) in human nasal mucosa. American Journal of Physiology 1990;258:L81-L88. Baraniuk JN, Lundgren J, Goff J, Peden D, Merida M, Shelhamer J, Kaliner MA. Gastrin releasing peptide (GRP) in human nasal mucosa. Journal of Clinical Investigations 1990;85:998-1005. Baraniuk JN, Okayama M, Lundgren JD, Mullol M, Merida M, Shelhamer JH, Kaliner MA. Vasoactive intestinal peptide (VIP) in human nasal mucosa. Journal of Clinical Investigations 1990;86:825-831. Baraniuk JN, Silver PB, Kaliner MA, Barnes PJ. Neuropeptide Y (NPY) is a vasoconstrictor in human nasal mucosa. Journal of Applied Physiology 1992;73:1867-1872. Baraniuk JN, Castellino S, Goff J, Lundgren JD, Mullol J, Merida M, Shelhamer JH, Kaliner MA. Neuropeptide Y (NPY) in human nasal mucosa. American Journal of Respiratory Cell and Molecular Biology 1990;3:165-173. Baraniuk JN, Ali M, Brody D, Maniscalco J, Wong G, Troost T, Mak J, Barnes PJ. Glucocorticoids induce 2-adrenergic receptors in human nasal mucosa in vivo and in vitro. American Journal of Respiratory and Critical Care Medicine 1997 (in press). Kesavanthan J, Swift DL, Bascom R. Nasal pressure-volume relationships determined with acoustic rhinometry. Journal of Applied Physiology 1995;79:547-553. Tomkinson A, Eccles R. Acoustic rhinometry: do we need a standardized operating procedure? Journal of Clinical Otolaryngol 1996;21:284-287.

Publications Details for: Nociceptive Dysfunction and Environmental Exposures Grant Number R825814 RFA: Issues in Human Health Risk Assessment (1997) Other views: Selected publication types Journal articles Publications submitted after final report Redisplay this page with Reference Title, Journal, and Author Columns Display this page in RIS format

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Maibach H, Naranch K, Repka-Ramirez SM, Pheiffer A, Hwang E, R825814 (Final) Clauw D, Baraniuk JN. Multiple chemical sensitivity in Chronic Fatigue Syndrome (CFS). Journal of Allergy and Clinical Immunology 2001;107:S27.

not available Abstract

(1)

Journal Article Baraniuk JN, Clauw D, Yuta A, Ali M, Gaumond M, Upadhyayula N, R825814 (Final) Fujita K, Shimizu T. Nasal secretion analysis in allergic rhinitis, cystic fibrosis, and nonallergic fibromyalgia/chronic fatigue syndrome subjects. American Journal of Rhinology 1998;12(6):435-440.

Abstract from PubMed

Abstract: Ingenta Connect

Journal Article Baraniuk JN, Naranch K, Maibach H, Clauw DJ. Irritant rhinitis in allergic, non-allergic, control, and Chronic Fatigue Syndrome populations. Journal of Chronic Fatigue Syndrome 2000;7(2):3-31. Journal Article Baraniuk JN, Naranch K, Maibach H, Clauw D. Tobacco sensitivity in Chronic Fatigue Syndrome. Journal of Chronic Fatigue Syndrome 2000;7(2):33-52. Paper

R825814 (Final)

not available not available Journal

Article (3)

R825814 (Final)

Tai C-F, Le U, Ali M, Baraniuk JN. Effects of fluticasone propionate on R825814 (Final) myeloperoxidase levels in nasal lavage fluids from sinusitis, allergic rhinitis, and normal subjects, 2002.

not available

http://www.ncbi.nlm.nih.gov/pubmed/9883301

Nasal secretion analysis in allergic rhinitis, cystic fibrosis, and nonallergic fibromyalgia/chronic fatigue syndrome subjects.
Baraniuk JN, Clauw D, Yuta A, Ali M, Gaumond E, Upadhyayula N, Fujita K, Shimizu T.

Am J Rhinol. 1998 Nov-Dec;12(6):435-40. Division of Rheumatology and Immunology and Allergy, Georgetown University, Washington, D.C. 20007-2197, USA.
Abstract

Rhinitis symptoms are present in approximately 70% of subjects with fibromyalgia and chronic fatigue syndrome (FM/CFS). Because only 35% to 50% have positive allergy skin tests, nonallergic mechanisms may also play a role. To better understand the mechanisms of nonallergic rhinitis in FM/CFS, nasal lavages were performed, and markers of vascular permeability, glandular secretion, and neutrophil and eosinophil infiltration measured in 27 nonallergic FM/CFS, 7 allergic rhinitis, 7 cystic fibrosis, and 9 normal subjects. Allergic rhinitis subjects had significantly increased vascular permeability (IgG) and ECP levels. Cystic fibrosis subjects had significantly higher elastase and total protein levels. There were no significant differences between FM/CFS and normal lavage fluids. Analysis of the constituents of nasal mucus provides information about ongoing secretory processes in rhinitis. There were no differences in the basal secretion of these markers of vascular permeability, submucosal gland serous cell secretion, eosinophil and

neutrophil degranulation in nonallergic FM/CFS subjects. This suggests that constitutively active secretory processes that regulate continuous production of nasal secretions are not altered in FM/CFS. Future studies should examine alternative mechanisms such as inducible, irritantactivated, or reflex-mediated effects.