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TOPIC: MCS af Etiology: Central Sensitization

MCS af Etiology: Central Sensitization 8 years 11 months ago #1

Structural and functional alteration of the airway epithelium and its sensory innervation result in central sensitization.

Rebecca Bascom. Environmental and Airway Diseases Research Facility, University of Maryland School of Medicine, Baltimore MD.


"...The structure of the C-fiber system and function of the neuroinflammatory system is altered in people reporting chemical sensitivity..."


"...Afferent nerves within the airways can be classified as glutamatergic or tachykinergic nerve fibres...

...Synaptic neurotransmission between vagal primary afferent nerves and second-order neurons occurs primarily within the nucleus of the solitary tract within the brainstem. The primary excitatory transmitter at this synapse is glutamate (Haxhiu 2000). Accordingly many airway afferent nerve fibres can be considered glutamatergic nerves...

...Many nociceptive C-fibres communicate with second-order neurons through the action of neurokinins (substance P, neurokinin A). Neurokinins are synthesized in the cell body and transported to the central and peripheral terminals. In the CNS, neurokinins can act to augment synaptic transmission through the interaction with G-protein coupled neurokinin receptors (NK1, NK2 and NK3) located on secondary neurons (Mazzone 2000)...

...In the periphery, release of neurokinins via axon reflexes can lead to neurogenic inflammatory reactions (McDonald 1988). Some C-fibres may branch to directly form synaptic contacts on local parasympathetic ganglion neurons. When neurokinins are released from these terminals, excitatory postsynaptic potentials occur on the principal parasympathetic neurons (Canning 2002, Myers 1996, Kummer 1992). This direct afferent autonomic postganglionic communication is often referred to as a ‘peripheral reflex’...

...Subsets of sensory nerves within the airways can contain transmitters and neuropeptides other than, or in addition to, neurokinins. These peptides include, among others, calcitonin gene related peptide, vasoactive intestinal peptide (Helki 1988), and neuropeptide Y (Kummer 1993)...

...the induction of neurokinin synthesis in afferent fibres which under normal conditions do not contain neurokinins. Inflammation is known to induce a qualitative switch in ‘touch fibres’ of the somatosensory system so that they, like nociceptive C-fibres, express substance P...

...Substance P released from the central terminals of these touch fibres appears to contribute to inflammatory hyperalgesia by enhancing transmission in the spinal cord and exaggerating the central response to normally innocuous stimuli (Neumann 1996)...

...There has been little attention given to how airway inflammation affects synaptic transmission between the primary afferent nerve and second-order neurons in the brainstem (NTS). The low threshold mechanosensors in the airway are thought to use excitatory amino acids (EAAs) as their neurotransmitters...

...When EAAs, such as glutamate are released onto second-order neurons in the brainstem they cause fast excitatory postsynaptic potentials. The efficacy with which the EAA produces synaptic transmission can be increased by the presence of neurokinins. This enhancement of synaptic transmission in the CNS has been termed ‘central sensitization’..."


"...central sensitization...activity or use dependent form of functional synaptic plasticity that resulted in pain hypersensitivity...triggered by the activity evoked in dorsal horn neurons by input from c-nociceptors...chemical activation of nociceptors by irritant compounds...the TRPA1 channel...TRPV1 channels...

...acute activity-dependent central sensitization was dependent on NMDA receptors (Woolf 1991), revealing a key involvement of glutamate and its receptors...

...the early phosphorylation-dependent and transcription-independent phase results mainly from rapid changes in glutamate receptor and ion channel properties. The later, longer-lasting, transcription-dependent phase drives synthesis of the new proteins responsible for the longer-lasting form of central sensitization observed in several pathological conditions (Woolf 2000)...

...Glutamate, the fast transmitter of primary afferent neurons, binds to several receptors on postsynaptic neurons in the dorsal horn of spinal cord, including ionotropic amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), N-methyl-D-Aspartate (NMDA), and Kainate (KA) receptors and several metabotropic (G-protein coupled) glutamate receptor subtypes (mGluR)...

...In the superficial laminae of the dorsal horn, AMPAR and NMDAR are present in virtually every synapse and are arranged in a mosaic-like manner, whereas mGluRs sit at the extremities of the postsynaptic density zone (PSD) (Alvarez 2000, Antai 2008, Azkue 2003, Pitcher 2007)...

...Activation of NMDAR is an essential step in both initiating and maintaining activity-dependent central sensitization as its blockade by noncompetitive (MK801) or competitive (D-CPP) NMDAR antagonists prevent and reverse the hyperexcitability of nociceptive neurons induced by nociceptor conditioning inputs (Ma 1995, Woolf 1991) and conditional deletion of NR1 abolishes NMDA synaptic inputs and acute activity-dependent central sensitization (South 2003)...

...NMDAR is both a trigger and effector of central sensitization. Under normal conditions, the NMDAR channel is blocked in a voltage-dependent manner by a magnesium (Mg2+) ion sitting in the receptor pore (Mayer 1984). Sustained release by nociceptors of glutamate and the neuropeptides substance P and CGRP leads to sufficient membrane depolarization to force Mg2+ to leave the NMDAR pore, whereupon glutamate binding to the receptor generates an inward current (Mayer 1984). Removal of this voltage-dependent block is a major mechanism for rapidly boosting synaptic efficacy and allows entry of Ca2+ into the neuron, which then activates numerous intracellular pathways that then contribute to the maintenance of central sensitization...

...In addition to the critical role of NMDAR in increasing the excitability of nociceptive neurons, activation of group I mGluRs by glutamate also appear important for the development of central sensitization. Although these receptors do not participate to basal nociception (Neugebauer 2000, Young 1997) their activation is necessary for activity-dependent central sensitization mediated by C-fibers (Azkue 2003, Derjean 2003, Lefebvre 2000, Soliman 2005, Young 1997, 1994)...

...In contrast, activation of group II-III mGluRs is associated with a reduction of capsaicin-induced central sensitization (Soliman 2005)...

...Substance P (SP), which is co-released with glutamate by unmyelinated peptidergic nociceptors, is also involved in the generation of central sensitization (Afrah 2002, Khasabov 2002, Ma 1995, Mantyh 1997, Willis 2002)...

...Substance P binds to the neurokinin-1 (NK1) G-protein–coupled receptor, which is expressed by spinothalamic, spinoparabrachial, and spino-PAG neurons (Gauriau 2002) and causes a long-lasting membrane depolarization (Giles 2007) and contributes to the temporal summation of C-fiber–evoked synaptic potentials (Dougherty 1991, Xu1992, Yaksh 1989) as well as to intracellular signaling...

...Ablation of NK1-positive neurons in the spinal cord leads to a reduction in capsaicin-evoked central sensitization, confirming the importance of projecting neurons expressing the substance P receptor in this phenomenon (Khasabov 2002, Mantyh 1997)...

...Calcitonin gene-related peptide (CGRP), also synthesized by small diameter sensory neurons, potentiates the effects of SP (Woolf 1986) and participates in central sensitization through postsynaptic CGRP1 receptors, which activate PKA and PKC (Sun 2004, 2003)...

...Nitric oxide (NO) synthesized by either neuronal or inducible NO synthases in the dorsal horn also has a role in central sensitization (Wu 2001, 1998, 1998a) Potential mechanisms for NO actions include the cGMP synthesis cascade, nitrosylation of membrane channels, ADP-ribosylation, and production of reactive species (Davis 2001, Schwartz 2008). The NO-cGMP pathway involves soluble guanylate cyclase, which is expressed by NK1-positive spinothalamic neurons, as well as inhibitory interneurons (Ding 2006)...

...The key features of acute activity-dependent central sensitization are that it is induced with a short latency (seconds) by intense, repeated, or sustained nociceptor inputs and typically lasts for tens of minutes to several hours in the absence of further nociceptor input...

...It generally requires activation of NMDA receptors for its induction, and these receptors contribute to its maintenance. Nevertheless, as reviewed above, multiple different triggers can contribute to the establishment of this form of central sensitization: glutamate acting on NMDAR, but also on AMPAR and mGluR, the neuropeptides substance P and CGRP, the kinin bradykinin, as well as BDNF and NO...

...Peripheral inflammation induces a phenotypic switch in primary sensory neurons that comprises a change in their neurochemical character and properties due to alterations in transcription and translation...

...Large DRG neurons begin, unlike in their naive condition, to express SP and BDNF when their peripheral terminals are exposed to inflammatory signals and nerve growth factor (NGF) (Mannion 1996 ,Neumann 1996). Consequently, activation of the myelinated fibers by low-intensity innocuous stimuli now releases these neuropeptides in the spinal cord, and conditioning stimulation of the afferents acquires the capacity to generate central sensitization, something they normally cannot do (Ma 1996, Mannion 1999, Neumann 1996)...

...After peripheral inflammation, Aβ-mediated synaptic input to superficial dorsal horn neurons is substantially increased from the very low levels found in noninflamed animals (Baba 1999)...

...TrkA-expressing nociceptors, instead of a phenotypic switch, begin to express higher levels of neuropeptides and other NGF-dependent proteins as a result of exposure to the increased NGF produced by inflammation (Woolf 2007, 1996)...

...the essence of central sensitization is a constantly changing mosaic of alterations in membrane excitability, reductions in inhibitory transmission, and increases in synaptic efficacy, mediated by many converging and diverging molecular players on a background of phenotypic switches and structural alterations..."

TRPA1 is shown to work with two key downstream events - increased glutamate at NMDA and synthesis of NO.


"...Icilin, previously named AG-3-5, is a cold-inducing compound, which elicits a dramatic, stimulant effect in rats. This effect is comprised of hyperthermia, hyperactivity, excessive grooming, and intense wet dog shaking (Cowan 1981,1978, Wei 1983,1981, Cowan 1981, Werkheiser 2007,2006) ...

...The ability of icilin to stimulate TRPM8 and TRPA1 channels designates the agent as a useful in vivo tool for investigating the physiological effects of cold-activated TRP channels and the role of endogenous neurotransmitter systems in those effects...(McKemy 2002, Peier 2002, Story 2003, Macpherson 2005, Liu 2006)...

...Our main aim was to investigate the hypothesis that nitric oxide production and NMDA receptor activation are required for icilin to evoke hyperthermia. Our hypothesis was based on evidence that nitric oxide and NMDA receptors play a key role in fever and drug-induced hyperthermia and that icilin increases extracellular glutamate in the brain (Amir 1991, Minano 1997, Roth 1998, Bowyer 2000, Benamar 2003, 2001, Rawls 2003, Werkheiser 2007. 2006)...

...the activation of these channels is positively coupled to two key downstream events - increased glutamatergic transmission at NMDA receptors and synthesis of NO. The identification of neurotransmitter systems that mediate the biological effects of cold-activated TRP channels may provide greater insight into the mechanism of action of cold receptor agonists (Biro 2005)...

...cold-activated TRP channels are positively coupled to downstream NMDA receptor activation. Microdialysis data showing that icilin causes a dose-dependent increase in extracellular glutamate in the rat striatum supports a functional link between cold-activated TRP channels and central glutamate systems ( Werkheiser 2007, 2006)...

...Prior work has established that glutamate, via a NMDA receptor mechanism, causes hyperthermia following its administration directly into the brain; modulates pyrogen- and stimulant-induced hyperthermia; and increases heat following its injection directly into the hypothalamus or midbrain raphe nuclei ( Amir 1989, Yoshimatsu 1993, Monda 1998, Bowyer 2000, Huang 2001, Rawls 2003, Cao 2006).

Thus, it is possible that TRPM8 and/or TRPA1 channel activation by icilin triggers an increase in extracellular glutamate in brain regions such as the hypothalamus and raphe nuclei which play a key role in thermoregulation following its administration directly into the brain; modulates pyrogen- and stimulant-induced hyperthermia; and increases heat production in brown adipose tissue following its injection directly into the hypothalamus or midbrain raphe nuclei which play a key role in thermoregulation.

The rise in extracellular glutamate causes NMDA receptor activation, leading to an increase in heat production in the brown adipose tissue and elevation in body temperature..."


"...The parietotemporal cortex, which has been related to MCS owing to electroencephalographic alterations found in this area (Bell 1998), is involved in the processing of complex aspects of attention and, in conjunction with the hippocampus, in the formation of memory (Bell 1996). Our finding of brain SPECT hypoactivity in these areas and also in frontal-subcortical circuits (Salmon 2001) could, in part, explain neurocognitive defects in MCS patients. Neurologic dysfunction observed prior to chemical exposure could point to persistent subclinical neurologic changes. In fact, basal SPECT brain cortical hypoactivity was found in our patients. In animal models, inflammation and permanent damage of the olfactory neuronal pathways could result from translocation of inhaled ultrafine particles to the brain (Elder 2006)..."

The threat is universal.


"...Breakdown of the nasal respiratory and olfactory epithelium and the BBB (Blood Brain Barrier) facilitates the access of systemic inflammatory mediators and components of air pollution to the central nervous system (CNS) (Calderon-Garciduenas 2004)..."

"...A coherent pathway linking exposure to air pollution and brain damage includes a chronic inflammatory process involving the respiratory tract, which results in a systemic inflammatory response with the production of inflammatory mediators capable of reaching the brain; continuous expression of crucial inflammatory mediators in the CNS at low levels; and the formation of reactive oxygen species (ROS) (Calderon-Garciduenas 2002, 2004; Calderon-Garciduenas, Maronpot 2003; Calderon-Garciduenas, Mora-Tiscareno 2003)..."

"...sustained exposures to significant levels of air pollutants including UFPM (ultrafine particulate matter) , PM2.5 (less than 2.5 microns), and PM-LPS produce brain neuroinflammation and neurodegeneration through at least four pathways..."

"...1 Induction of upper respiratory, lung epithelial, and endothelial injury leading to persistent chronic inflammation in the respiratory tract and systemic inflammation. The systemic inflammation is accompanied by the production of pro-inflammatory cytokines such as TNF alpha, IL 6 and IL-1beta...these cytokines can activate endothelial cells in the BBB, disrupt the BBB...and trigger cascades...results in increased expression of nitric oxide synthase...and nitric oxide production that opens the BBB..."

"...2 We strongly support the importance of the olfactory pathway...since olfactory neurons are loaded with PM...will potentially translate into an abnormality in the limbic system...(Bedard 2004)..."

"...3 The vagus/trigeminal (Lewis 2005) pathways are also crucial, given that PM enters the respiratory and digestive systems..."

"...4 Direct access of UFPM to the brain, further accentuating an inflammatory response in the brain parenchyma..."

In combination with a genetic predisposition of the airway epithelium and its sensory innervation (Eberling 2009, Veronesi 2001, 2000, Roy 2000, Miyabara 1998, Jung 1921) -

MCS is usually caused by exposure to a continuous combustion byproduct aerosol - diesel and other exhaust, woodsmoke, and tobacco smoke - including particle agglomerates with adsorbed hydrocarbons and singlet nonagglomerated nanoparticles

Deering-Rice 2011, Hazari 2011, Li 2011, Taylor-Clark 2010, Baulig 2009, 2003a, Calderon-Garciduenas 2008, 2000, Veronesi 2003, 2002a, 2002b, 2001, 2000, 1999a, 1999b, Agopyan 2003, Bonvallot 2001, 2000, Gerde 2001, 1997, Oortgiesen 2000, Roy 2000, Miyabara 1998,1998a, Steerenberg 1998, Meggs 1997

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Fine particles expected to reach the CNS via trigeminal and olfactory nerve pathways

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