Itch
Itch is primarily mediated by slower conducting C-fibers innervating the dorsal horn of the spinal cord. Early itch studies used spicules of cowhage to show that the strongest itch is felt in the dermo-epidermal juncture area, the area where unmyelinated sensory fibers innervate [
10,
26]. Five percent of the C-fibers innervating the skin react to puritogenic application, with distinct populations of C-fibers corresponding to itch in individual nerve C-fiber recordings in humans [
24,
27]. Itch sensing C-fibers slowly conduct action potentials (0.5 m/s) and innervate large territories of skin [
27]. When C-fibers are desensitized with pretreatment of capsaicin, itch is greatly reduced or blocked [
28].
However, not all C fibers respond equally to all pruritogens. C-fibers can be divided into subcategories according to their response to various stimuli and these subcategories respond differently to different pruritic stimuli. C-fibers classified as mechanical and heat responsive (CMH) have been shown to respond to cowhage and histamine [
29]. Mechanically-insensitive C-fibers that respond to histamine (CMiHis+) have a preferential, not exclusive, activation to pruritic substances such as histamine and prostaglandin E(2) (PGE2) and substances that activate more of these specific CMiHis+ fibers are considered more potent pruritic agents [
19]. Microneurography recordings of C-fibers in human volunteers show that cowhage activates mechanosensitive C-fibers while histamine activates mechano-insensitive units. Capsaicin activates fibers in both classes [
24]. So cowhage induces itch through a different set of C-fibers than histaminergic itch. The activation of two different subsets of C-fibers shows that there are multiple pathways for pruritus, changing according to the stimulus.
Cough
C-fibers are also involved in the generation of cough. It is thought that C-fibers are important to a second type of cough, which is used to get rid of an itchy feeling in one’s throat. This feeling is more typical of chronic cough [
12]. Cough is generated when vagal C-fibers and myelinated cough receptors are activated [
20]. The C-fibers form a loose network in the airway mucosa with branches found in deeper lung structures [
7]. The majority of C-fibers innervating the airway arise from the vagus nerve, however there is also some innervation by spinal afferent C-fibers whose cell bodies are in the DRG [
30]. There are two sets of vagal C-fibers, the bronchial C-fibers which innervate the large airways and the pulmonary C-fibers which innervate the smaller, peripheral lung tissue [
30]. Collectively these C-fibers are the bronchopulmonary C-fibers and can be activated using a variety of chemical stimuli, including capsaicin, bradykinin and protons. Inhalation of these chemicals such as capsaicin in humans causes an itchy feeling in the airway and evokes cough [
12,
20,
31,
32]. In single fiber recordings, all vagal C-fibers tested respond to capsaicin and capsaicin-sensitive C-fibers are found in both the nodose and jugular ganglion [
7,
16]. However, in dogs and rats, rapid shallow breathing is caused by C-fiber activation, but not cough, showing that there can be species differences [
3,
14,
33]. In fact, C-fiber activation can inhibit mechanically induced cough [
14]. These inhibitory C-fibers are thought to be the C-fibers with cell bodies in the nodose ganglion. Indeed, activation of nodose C-fibers with adenosine reduce citric acid evoked cough [
20]. This implies that the jugular ganglia C-fibers are the ones playing an excitatory role in cough. The differences seen in C-fibers originating from the nodose ganglia versus C-fibers originating from the jugular ganglia are evidence of a multi-faceted cough reflex with many ways to fine-tune a response. However, the fact that many C-fiber activators cause cough in awake guinea pigs and humans, speaks to their role in generating cough.
Anatomically, the chemosensitive C-fibers extend numerous terminals superficially into the airway epithelium, placing them in an ideal position to react to inhaled chemical irritants [
34]. Labeling studies in guinea pigs show C-fibers terminating underneath the airway epithelium, with swelling suggestive of the presence of synaptic vesicles filled with Substance P (SP), Calcitonin gene related peptide (CGRP) and Neurokinin A [
21]. When the fibers innervating the tracheal epithelium are analyzed, nearly all C-fibers have cell bodies in the jugular ganglion and 60% are containing fibers [
32,
35]. These jugular C-fibers promote coughing [
20]. No peptide positive fibers are found in the nodose ganglion [
32,
36]. So within the C-fibers there are two subsets, peptidergic (in jugular ganglion) and non-peptidergic (in nodose ganglion) [
37]. However, the C-fibers that innervate the lungs (below the trachea) originate from both ganglia, with over 60% of C-fibers in the lungs found in the nodose ganglion [
7].
Many argue that direct cough is caused by the touch sensitive Aδ-fibers and that C-fibers cause cough by indirect mechanisms. This is shown by C-fiber evoked cough’s sensitivity to anesthesia. Anaesthetized animals often do not cough upon application of C-fiber stimulants but cough when awake. Stimulation of bronchopulmonary C-fibers with chemical stimuli can result in bronchoconstriction and mucous production, both of which can cause cough [
38]. Stimulated C-fibers release which mediates nitric oxide and results in an increase in fluid in airways, activating RARs and causing cough [
39]. It was found that pretreatment with a C-fiber stimulant, while not evoking cough alone, decreased the cough threshold for RAR and cough receptor stimulation. Conversely, desensitizing C-fibers with capsaicin application, led to a decrease in coughing upon myelinated cough fiber activation [
40]. These findings suggest a synergistic central interaction between C-fibers and myelinated RARs and cough receptors.
With the knowledge that C-fibers are involved in both itch and cough, it is likely that there are similarities to be found in activation of these sensory neurons. Large territories of innervation by C-fibers are seen in both the skin and lung. The jugular ganglion is derived from the neural crest, just like the dorsal root ganglion. With similar embryonic starts, these fibers may share many characteristics. Neural crest derived vagal nerves are seen innervating the large extrapulmonary airways while placodal nerves are seen innervating deeper lung tissue leading to speculation that the more superficial neural crest derived vagal nerves are responsible for reacting to external environmental stimuli [
7,
37]. This parallels the more superficial termination of C-fibers in the skin that are thought to be responsible for itch [
41].
Knowing that itch and cough are mediated by similar sensory neurons, the specifics of activating these fibers can be examined and compared. Two types of receptors are activated on sensory fibers, ionotropic and metabotropic. In both of these categories, itch and cough work through the same receptors in multiple instances. Table
1 lists some of the known pruritic and tussive agents and modulators as well as their pathways.
Table 1
Activators and modulators of itch and cough pathways
Bradykinin | B1, B2 | Weakly, modulator | Yes, modulator |
Capsaicin | TRPV1 | superficial application, Yes, modulator | Yes |
Oxidative | TRPA1 | Yes | Yes, modulator |
Cowhage | PAR2, PAR4 | Yes | Yes |
Histamine | H1, H4 | Yes, modulator | Modulator |
Proteases | PAR1, PAR2, PAR4 | Yes | Modulator |
Serotonin | 5HT2, 5HT3 | Yes | Modulator |
Substance P | NK1, NK2 | Yes | Modulator |