Environmental Health Perspectives 105, Supplement 2, March 1997

Neurogenic Inflammation: With Additional Discussion of Central and Perceptual Integration of Nonneurogenic Inflammation

Rebecca Bascom,1 William J. Meggs,2 Mark Frampton,3 Kenneth Hudnell,4 Kaye Killburn,5 Gerd Kobal,6 Michelle Medinsky,7 and William Rea8

1 Environmental and Airway Diseases Research Facility, University of Maryland School of Medicine, Baltimore, Maryland
2 Department of Emergency Medicine, East Carolina University, Greenville, North Carolina
3 Department of Pulmonary and Critical Care, University of Rochester School of Medicine, Rochester, New York
4 U. S. Environmental Protection Agency, Research Triangle Park, North Carolina
5 University of Southern California, Los Angeles, California
6 Department of Pharmacology and Toxicology, University of Erlangen-Nuremberg, Erlangen, Germany
7 Chemical Industry Institute of Technology, Research Triangle Park, North Carolina
8 Environmental Health Center, Dallas, Texas

Abstract
The Working Group on Neurogenic Inflammation proposed 11 testable hypotheses in the three domains of neurogenic inflammation, perceptual and central integration, and nonneurogenic inflammation. The working group selected the term people reporting chemical sensitivity (PRCS) to identify the primary subject group. In the domain of neurogenic inflammation, testable hypotheses included: PRCS have an increased density of c-fiber neurons in symptomatic tissues; PRCS produce greater quantities of neuropeptides and prostanoids than nonsensitive subjects in response to exposure to low-level capsaicin or irritant chemicals; PRCS have an increased and prolonged response to exogenously administered c-fiber activators such as capsaicin; PRCS demonstrate augmentation of central autonomic reflexes following exposure to agents that produce c-fiber stimulation; PRCS have decreased quantities of neutral endopeptidase in their mucosa; exogenous neuropeptide challenge reproduces symptoms of PRCS. In the domain of perceptual and central integration, testable hypotheses included: PRCS have alterations in adaptation, habituation, cortical representation, perception, cognition, and hedonics compared to controls; the qualitative and quantitative interactions between trigeminal and olfactory systems are altered in PRCS; higher integration of sensory inputs is altered in PRCS. In the domain of nonneurogenic inflammation, testable hypotheses included: increased inflammation is present in PRCS in symptomatic tissues and is associated with a heightened neurosensory response; PRCS show an augmented inflammatory response to chemical exposure. The working group recommended that studies be initiated in these areas. -- Environ Health Perspect 105(Suppl 2):531-537 (1997)

Key words: neurogenic inflammation, perceptual and central integration, inflammation, chemical sensitivity

This manuscript has been reviewed by the U.S. Environmental Protection Agency and approved for publication. Mention of trade names and commercial products does not constitute endorsement or recommendation for use.This paper is based on a work group discussion at the Conference on Experimental Approaches to Chemical Sensitivity held 20-22 September 1995 in Princeton, New Jersey. Manuscript received at EHP 14 August 1996; manuscript accepted 24 January 1997.
Address correspondence to Dr. R. Bascom, 10 S. Pine Street. Room 800, Baltimore, MD 21201. Telephone: (410) 706-2169. Fax: (410) 706-8162. E-mail: bascom@umabnet.umd.ab.edu
Abbreviations used: Ach, acetylcholine; CGRP, calcitonin gene related peptide; CO2, carbon dioxide; MCS, multiple chemical sensitivity; NKA, neurokinin A; Nor, norepinepherine; NPY, neuropeptide Y; PRCS, people reporting chemical sensitivity; sub P, substance P; VIP, vasoactive intestinal peptide.

Introduction

 The goal of the Working Group on Neurogenic Inflammation was to formulate specific testable hypotheses to explain the relationship between exposure and symptoms in people reporting chemical sensitivities. The working group designated people reporting chemical sensitivity (PRCS) as the phrase to identify the group of primary interest. For specific research projects, the working group emphasized the importance of certain hypotheses, clearly stated subject selection criteria, uniform subject characterization methods, and inclusion of appropriate controls.

figure 1

Figure 1. Potential interactions between chemical sensitivity and the domains of neurogenic inflammation, perceptual and central integration, and nonneurogenic inflammation.

The group identified three broad domains in which hypotheses could be generated: neurogenic inflammation, perceptual and central integration, and inflammation. Neurogenic inflammation was the initial assigned task of the group. However, some group members thought perceptual and central integration or nonneurogenic inflammation likely were the domain of primary dysfunction. Figure 1 indicates the likely interactions between these three domains.

The working group focused on understanding symptoms and processes that occur minutes, hours, or days after low-level chemical exposure. The group limited experimental questions to those that could be performed using existing methods and techniques. In the future techniques such as functional imaging may be useful but are insufficiently developed at present. Reagents for immunohistochemistry and immunoassays, and pharmacologic agents for human use are also developing rapidly.

The group thought individual research groups should specify their own definitions of chemical sensitivity but draw from previously proposed definitions. Subjects with diagnosed diseases may be included in research if controls include diseased subjects with and without chemical sensitivity. Studies may include subject groups with rhinitis and asthma, for which measures of short-term responses are well developed. Subjects with known psychiatric disease may also be included.

This paper presents definitions and general considerations for experimental design and methods, followed by considerations specific to the domains of neurogenic inflammation, perceptual and central integration, and inflammation. Also included are the rationale for potential involvement of the domain, specific hypotheses, and selected references.

Definitions

People reporting chemical sensitivity: The primary research subject group. The term multiple chemical sensitivity (MCS) or MCS-syndrome can be used as a research term provided there is an explicit research definition. The phrase chemical sensitivity may reflect several alterations in exposure-response relationships. Figure 2 illustrates terminology. The terms have been chosen because committee members thought they had common usage across disciplines of physiology and psychology.

figure 2

Figure 2. Illustration of terminology. (A) More sensitive denotes a decrease in the magnitude of exposure required to initiate the response; more reactive denotes an increase in the slope or in the maximum level of the exposure-response curve. (B) The threshold for perceiving symptoms may occur in the mid-position of the exposure-response curve (T). As a result, the clinical report of increased sensitivity could mean that the individual has become more reactive (R) or more sensitive (S). (C) Recognition of symptoms may require that the response be present for a certain duration. The clinical report of increased sensitivity could mean that the response has become more prolonged. (D) Habituation is the decrease in the amplitude of the response that occurs with repeated presentation of a stimulus. Adaptation is a progressive decrease in the magnitude of the response with prolonged presentation of a stimulus. The term adaptation is sometimes used to describe both adaptation and habituation, as defined above.

         Irritation: An excessive response to stimulation, i.e., specifically a condition of soreness or inflammation. Many chemicals stimulate c-fiber nerves; patients report having excessive responses. At present, it is unknown whether the response is characterized by soreness (acute discomfort) or induction of inflammation.

         Increased response: An inclusive term that can mean increased sensitivity, increased reactivity, and prolonged duration.

         Increased sensitivity: A leftward shift in the exposure-response curve.

         Increased reactivity: An increase in the slope or the maximum of the exposure-response curve.

         Increased duration: An increase in the duration of the response.

         Threshold for symptoms: The point on the exposure-response curve at which symptoms are reported by the subject.

         Habituation: Over time, the repeated presentation of a stimulus elicits a response of diminished amplitude.

         Adaptation: The tendency, characteristic of a sensory organ, to show a diminished response as a result of prolonged or short-term repetitive stimulation.

         Peripheral neural pathways: Peripheral nerves innervating organs contain both afferent and efferent neural pathways. Chemosensitive c-fiber nerves are afferent nerves that may have efferent functions through the axon reflex (Figure 3). Neuropeptides contained in c-fiber nerves include substance P (sub P), calcitonin gene-related peptide (CGRP), and neurokinin A (NKA). Efferent nerves include the sympathetic nerves and parasympathetic nerves. Sympathetic neurotransmitters include norepinephrine (Nor) and neuropeptide Y (NPY). Parasympathetic nerves contain acetylcholine and vasoactive intestinal peptide (VIP). The importance of each neural pathway in overall organ function or specific cell function depends on the density of nerve fibers, proximity to target sites, and the presence of specific receptors on target tissues.

figure 3
Figure 3. Anatomic elements of the response to chemosensitive nerve stimulation. Stimulation of the c-fiber nerves results in a peripheral axon reflex with release of neuropeptides sub P, CGRP, and NKA. The neuropeptides may be inactivated by neutral endopeptidase, an enzyme present in the mucosa, or may bind to receptors present on the epithelium, glands, smooth muscle, or vessels. Stimulation of the nerves may also result in a central afferent stimulus, with activation of parasympathetic nerves and sympathetic nerves. The neurotransmitters for these nerves are Ach and VIP (parasympathetic) and Nor and NPY (sympathetic).

         Trigeminal nerve: The trigeminal nerve innervates the face and divides into the ophthalmic, maxillary, and mandibular branches (1). The trigeminal nerve innervates the respiratory mucosa that first contact inhaled irritants. The trigeminal nerve contains afferent and efferent nerves. Upper respiratory tissue is densely innervated with c-fiber nerves in the epithelium, glands, and vessels (1). Neuropeptide receptors are widespread in mucosal tissues. Efferent cholinergic fibers typically stimulate glandular secretion, whereas adrenergic fibers alter vascular tone.

         Neurogenic inflammation: Neurogenic inflammation is initiated by stimulation of peripheral c-fiber neurons (2-4) (Figure 3). A peripheral axon reflex results in the release of neuropeptides and in sig