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. 2007 Dec;211(6):775–783. doi: 10.1111/j.1469-7580.2007.00821.x

Distribution of TRPV1- and TRPV2-immunoreactive afferent nerve endings in rat trachea

Yoshio Yamamoto 1, Yoshikazu Sato 2, Kazuyuki Taniguchi 2
PMCID: PMC2375849  PMID: 17979952

Abstract

Nociception in the trachea is important for respiratory modulation. We investigated the distribution, neurochemical characteristics, and origin of nerve endings with immunoreactivity for candidate sensor channels, TRPV1 and TRPV2, in rat trachea. In the epithelial layer, the intraepithelial nerve endings and dense subepithelial network of nerve fibers were immunoreactive for TRPV1. In contrast, TRPV2 immunoreactivity was observed mainly in nerve fibers of the tracheal submucosal layer and in several intrinsic ganglion cells in the peritracheal plexus. Double immunostaining revealed that some TRPV1-immunoreactive nerve fibers were also immunoreactive for substance P or calcitonin gene-related peptide, but neither neuropeptide colocalized with TRPV2. Injection of the retrograde tracer, fast blue, into the tracheal wall near the thoracic inlet demonstrated labeled neurons in the jugular, nodose, and dorsal root ganglia at segmental levels of C2–C8. In the jugular and nodose ganglia, 59.3% (70/118) and 10.7% (17/159), respectively, of fast blue-labeled neurons were immunoreactive for TRPV1, compared to 8.8% (8/91) and 2.6% (5/191) for TRPV2-immunoreactive. Our results indicate that TRPV1-immunoreactive nerve endings are important for tracheal nociception, and the different expression patterns of TRPV1 and TRPV2 with neuropeptides may reflect different subpopulations of sensory neurons.

Keywords: ion channel, mechanotransduction, respiratory tract, sensory nerve, TRPV1, TRPV2

Introduction

Several different nerve receptors in the respiratory tract initiate the respiratory reflex, including nociceptors and rapidly adapting receptors (RARs) (Undem et al. 2002). Nociceptors arise from nonmyelinated C fibers or thin-myelinated Aδ fibers, are stimulated by capsaicin and acidity, and induce apnea (Widdicombe, 1998; Lee et al. 2003; Canning et al. 2004). Nociceptors are distributed throughout the tracheobronchial tree and terminate within the epithelial layer. They contain several neuropeptides, such as substance P (SP), neurokinin A, and calcitonin gene-related peptide (CGRP) (Widdicombe, 1998, 2001; Barnes, 2001; Undem et al. 2002). In contrast, RARs conduct action potentials in the Aδ range and are stimulated by mechanical displacement of airway mucosa and by acidity, but not by capsaicin (Widdicombe, 2003). RARs are distributed mainly under the epithelial region of the hilum and carina (Widdicombe, 2003). RARs initiate the cough reflex in some species including guinea-pig, dog, and cat. In addition, these receptors cause hyperventilation and tachypnea in rat (Korpas & Timori, 1979).

The nonselective cation channel TRPV1 has been suggested to mediate the initial response of nociceptors (Caterina et al. 1997). TRPV1 is activated by various stimuli such as capsaicin, protons, and moderate heat (> 43 ºC) to release neuropeptides, which then elicit neuroinflammatory actions such as extravasation and bronchoconstriction in airway tissues (Barnes, 2001). In contrast, TRPV1 analogue, TRPV2, is activated by noxious heat (> 52 ºC) and membrane stretching (Caterina, 1999; Muraki et al. 2003; O’Neil & Heller, 2005). Current knowledge about ion channels in the RARs remains limited (Kollarik & Undem, 2006); those activated by acidity, acid-sensing ion channels (ASIC), and TRPV2 seem to be the candidate mediators of initial RAR activation.

TRPV1 and TRPV2 are both distributed in sensory neurons of the dorsal root ganglion, the jugular and nodose ganglion of the vagus, and the trigeminal ganglion (Caterina et al. 1997, 1999; Guo et al. 1999; Ma, 2001, 2002; Ichikawa & Sugimoto, 2003; Lewinter et al. 2004). In peripheral tissues, TRPV1-immunoreactive nerve endings were observed in the respiratory tract (Koike et al. 2004; Yamamoto & Taniguchi, 2005; Watanabe et al. 2005, 2006), gastrointestinal tract (Anavi-Goffer & Coutts, 2003; Patterson et al. 2003; Ward et al. 2003), urinary tract (Avelino et al. 2002), and skin (Guo et al. 1999). Free nerve endings showing TRPV1 immunoreactivity in the respiratory tract are also localized to the laryngeal and tracheobronchial epithelia (Yamamoto & Taniguchi, 2005; Watanabe et al. 2005, 2006), and a small number of TRPV2-immunoreactive nerve endings have been observed in the laryngeal mucosa (Yamamoto & Taniguchi, 2005). Retrograde tracer experiments revealed that nerve endings in the trachea and lung originate from the jugular and nodose ganglia of the vagus and dorsal root ganglion, and that the majority of SP- and/or CGRP-containing neurons are located in the jugular ganglia of guinea-pig (Kummer et al. 1992) and rat (Springall et al. 1987). Furthermore, electrophysiological studies in guinea-pig suggested that most extrapulmonary nociceptors originate from the jugular ganglion (Undem et al. 2004). However, nerve fibers and/or endings with TRPV1- and TRPV2-immunoreactivity in the lower respiratory tract remain uncharacterized with respect to distribution, colocalization with neuropeptides such as SP and CGRP, and cellular origin.

The present study examined the distributions of TRPV1 and TRPV2 immunoreactivity in nerve endings of rat trachea and lung. Colocalization of TRPV1 or TRPV2 with SP or CGRP was used to map the neurochemical characteristics of the nerve endings. Retrograde tracing with fast blue (FB) was used also to identify the cellular origin of the tracheal nerve endings immunoreactive for TRPV1 or TRPV2.

Materials and methods

Materials

Male Wistar rats (8 weeks old, n = 15) were used in the present study. All protocols were approved by the local ethics committee.

Immunohistochemistry

For immunohistochemistry, six rats were anesthetized by pentobarbital (15 mg kg−1; intraperitoneal injection) and transcardially perfused with Ringer's solution (500 mL) followed by Zamboni's fixative (4% paraformaldehyde, 0.5% picric acid in 0.1 m phosphate buffer; pH 7.4, 500 mL). The trachea and lung were dissected out and fixed in the same fixative for 3 h. The tissues were then immersed in 30% sucrose in phosphate-buffered saline (PBS; pH 7.4) and frozen for serial cryosectioning at 10 µm. Sections were collected on glass slides coated with chrome-alum gelatin. The sections were incubated for 60 min with non-immune donkey serum (1 : 50), and rinsed with PBS. The sections were then incubated overnight at 4 ºC with rabbit polyclonal antisera to TRPV1 (EDAEVFKDSMVPEGK; synthetic peptide corresponding to amino acids 824–838 from rat TRPV1) or TRPV2 (KNSASEEDHLPLQVLQSP; synthetic peptide corresponding to amino acids 744–761 from rat TRPV2). Antibody details are summarized in Table 1. After incubation, the sections were washed again with PBS, and incubated with TRITC-labeled donkey anti-rabbit IgG for 2 h at room temperature. After washing with PBS, sections were mounted in glycerol-PBS and examined by epifluorescence microscopy (E-600, Nikon, Tokyo, Japan). Negative controls were incubated with preabsorbed antibody or PBS instead of primary antisera.

Table 1.

Antibodies used in the present study

Code Host species Dilution Source
Primary antibodies
 TRPV1 Ab-1 Rabbit 1 : 100 A
 TRPV2 ab6183 Rabbit 1 : 200 B
 Substance P AB5892 Guinea pig 1 : 5000 C
 Calcitonin gene-related peptide 03-16010 Guinea pig 1 : 10 000 D
Secondary antibodies
 TRITC-conjugated anti-rabbit IgG (H+L) 711-025-152 donkey 1 : 100 E
 FITC-conjugated anti-guinea-pig IgG (H+L) 705-095-148 donkey 1 : 100 E
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A, Calbiochem, San Diego, CA; B, Abcam, Cambridgeshire, UK; C, Chemicon, Temecula, CA; D, American Research Products, Belmont, MA; E, Jackson Immunoresearch, West Grove, PA.

Double immunofluorescence

Frozen sections were also subjected to double immunostaining for TRPV1 or TRPV2 and SP or CGRP. After incubation with normal donkey serum, sections were incubated with rabbit polyclonal anti-TRPV1 or anti-TRPV2 antibodies together with guinea-pig antibodies to SP or CGRP for 15 h at 4 ºC. Sections were washed and then incubated with a mixture of TRITC-labeled donkey anti-rabbit IgG and FITC-labeled donkey anti-guinea-pig IgG for 2 h at 25 ºC. The sections were coverslipped with glycerol-PBS, and examined by epifluorescence microscopy. Details of antibodies are summarized in Table 1.

Retrograde labeling

Five rats were anesthetized with pentobarbital (15 mg kg−1; intraperitoneal injection) and the neck was incised to expose the trachea. The trachea was cut open at the midline (5 mm), then a retrograde tracer (2.5% fast blue in 10% dimethylsulfoxide; FB, Polysciences, Warrington, PA) was injected into the submucosal layer of the tracheal wall near the thoracic inlet using a thin glass micropipette connected to a microinjector (IM-9B, Narishige, Tokyo, Japan) at three to five loci, with a total injection volume of 4 µL. Wounds were then sutured, and 5 days later the animals were fixed by transcardial perfusion as described above. The jugular, nodose, and dorsal root ganglia were dissected out from segmental level C1 to Th2. Semi-serial 10 µm sections from these tissues (50 µm at intervals) were immunostained for TRPV1 or TRPV2. Epifluorescence microscopy was used to analyze area profiles of FB-labeled neurons using Scion Image software (Scion Corp, Frederick, MD).

Results

Immunohistochemistry

Numerous nerve fibers in the trachea and extrapulmonary bronchus showed TRPV1 immunoreactivity (Fig. 1A–F). In the epithelium, immunopositive nerve endings were located in the intraepithelial layer and dense subepithelial network containing the source nerve fibers (Fig. 1A,B,E). There were similar number of TRPV1-immunoreactive intraepithelial nerve endings in the cartilaginous and membranous regions and among the cranial, middle, and caudal parts. TRPV1-immunopositive nerve fibers in the submucosa were scarce (Fig. 1A,C), with some found around the strands of tracheal muscle, but only a few within the tracheal muscle (Fig. 1C) or perivascular nerve plexus (Fig. 1D). In the peritracheal nerve plexus, no TRPV1 immunoreactivity was found in nerve cell bodies but some nerve fibers in the ganglia showed staining (Fig. 1F). In the intrapulmonary bronchi, TRPV1-immunoreactive nerve fibers were found from the lobar bronchi to alveolar sac (Fig. 1G–I), whereas only intraepithelial nerve endings showed TRPV1 immunoreactivity in the lobar and segmental bronchi (Fig. 1G). Immunostaining for TRPV1 was diffusely distributed in the nerve fibers of the submucosal layer and around the bronchial muscles (Fig. 1G). The terminal and respiratory bronchioli showed TRPV1 immunoreactivity in the nerve fibers beneath the epithelial layer (Fig. 1H,I), and the nerve strands containing TRPV1-immunoreactive fibers ran through the interalveolar septa (Fig. 1H).

Fig. 1.

Fig. 1

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TRPV1 immunoreactivity in rat trachea (A–F) and intrapulmonary bronchi (G–I). (A) Cross-section of the tracheal cartilaginous wall. TRPV1-immunoreactive free nerve endings (arrows) and nerve fibers (arrowheads) are shown in the epithelial layer (E) and submucosal layer (SM), respectively. TC, tracheal cartilage. (B) Tangential section of the tracheal mucosa showing a dense network of subepithelial nerves with TRPV1 immunoreactivity. (C) TRPV1-immunoreactive nerve fibers (arrows) around the tracheal muscle (TM) (D) TRPV1-immunoreactive subepithelial nerve network beneath the epithelial layer (E). A few immunoreactive nerves (arrows) are also present around the blood vessel. (E) High-magnification view of TRPV1-immunoreactive intraepithelial nerve endings that terminate near the free border. (F) TRPV1-immunoreactive nerve fibers (arrows) in the peritracheal ganglion. Nerve cell bodies are negative for TRPV1 (arrowheads). (G) TRPV1 immunoreactivity in the lobar bronchus. Note the free nerve endings in the epithelial layer (arrows) and nerve fibers around the bronchial muscle (arrows). BM, bronchial muscle. (H) TRPV1-immunoreactive nerve fibers in the submucosal layer of terminal bronchiole (arrow) and interalveolar septum (arrowheads). TB, terminal bronchiole; AS, alveolar sac; I, TRPV1-immunoreactive nerve fibers (arrow) in the subepithelial layer of respiratory bronchiole (RB).

TRPV2-immunoreactive nerve fibers were mainly distributed in the submucosal layer of the trachea, and were fewer in number than TRPV1-immunoreactive fibers (Fig. 2A,B). In the epithelial layer, TRPV2 immunoreactivity was observed in a few intraepithelial nerve endings (Fig. 2C), but intense staining was present in some epithelial cells (Fig. 2A,B). The nerve strands of the peritracheal plexus and submucosal layer showed TRPV2 immunoreactivity in a few varicose nerve fibers (Fig. 2A,C). Immunoreactivity was also observed in nerve fibers within the tracheal muscle (Fig. 2A), and in several intrinsic ganglion cells of the peritracheal plexus (Fig. 2D).

Fig. 2.

Fig. 2

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TRPV2 immunoreactivity in the epithelial and submucosal layers of rat trachea. (A) TRPV2-immunoreactive nerve fibers within the tracheal muscle (small arrows) and the peritracheal plexus (large arrows). Numerous TRPV2-immunoreactive epithelial cells (arrows) are also apparent in the epithelial layer (E). TM, tracheal muscle. (B) TRPV2-immunoreactive nerve fibers (arrows) in the submucosal layer (SM). TRPV2-immunoreactive epithelial cells (arrows) are also present in the epithelial layer (E). (C) A few intraepithelial nerve endings (arrow) are immunoreactive for TRPV2. (D) TRPV2 immunoreactivity in both nerve cell bodies (arrowheads) and nerve fibers (arrows) in the peritracheal ganglion.

Negative controls showed no TRPV1- or TRPV2-positive staining.

Double immunofluorescence

Sections double-labeled for TRPV1 and SP or CGRP showed colocalization of both SP and CGRP with TRPV1 in the intraepithelial nerve endings and subepithelial nerve network (Fig. 3A–F), although some TRPV1-immunoreactive nerve fibers were not immunoreactive for either SP (Fig. 3A–C) or CGRP (Fig. 3D–F). Conversely, some CGRP-immunoreactive nerve fibers were not positive for TRPV1, whereas most of the SP-immunoreactive nerve fibers were TRPV1-positive. In contrast, TRPV2 showed no colocalization with SP or CGRP (Fig. 3G–L).

Fig. 3.

Fig. 3

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Double immunofluorescence for TRPV channels and neuropeptides. Right panels (C,F,I,L) are merged figures of left (A,D,G,J) and center (B,E,H,K) panels. (A–C) Double immunofluorescence for TRPV1 and SP. Some TRPV1-immunoreactive nerve endings are also immunoreactive for SP (arrow), but others are SP-negative (arrowhead). (D–F) Double immunofluorescence for TRPV1 and CGRP. Some TRPV1-immunoreactive nerve endings are also immunoreactive for CGRP (arrows), whereas others are CGRP-negative (arrowhead). Furthermore, some CGRP-immunoreactive nerve fibers are immunonegative for TRPV1 (double arrowhead). (G–I) Double immunofluorescence for TRPV2 and SP. TRPV2-immunoreactive nerve fibers (arrow) did not correspond to SP-immunoreactive nerves (arrowheads). (J–L) Double immunofluorescence for TRPV2 and CGRP. TRPV2-immunoreactive nerve fibers (arrow) ran together with CGRP-immunoreactive nerves (arrowheads), but did not correspond with each other.

Retrograde labeling

FB injected into the tracheal wall near the thoracic inlet labeled neurons in both jugular and nodose ganglia, and a small number in the dorsal root ganglia at segmental level C2–C8. TRPV1 immunoreactivity was observed in 59.3% (70/118) and 10.7% (17/159) of FB-labeled neurons in the jugular and nodose ganglia, respectively, from five rats (Fig. 4A), and 8.8% (8/91) and 2.6% (5/191) of the same neurons, respectively, were immunoreactive for TRPV2 (Fig. 4B). TRPV1-immunoreactive neurons labeled with FB varied in size in the jugular and nodose ganglia (Fig. 5): 175.4–1727.5 µm2 (mean ± SD, 694.6 ± 349.7 µm2) in the jugular ganglion and 403.5–1154.2 µm2 (668.2 ± 179.3 µm2) in the nodose ganglion. In the dorsal root ganglion, equivalent neurons were smaller in size (Fig. 5C). On the other hand, the TRPV2-immunoreactive neurons labeled with FB measured 421.1–1269.4 µm2 (754.8 ± 291.8 µm2) in the jugular ganglion and 486.3–1244.9 µm2 (781.2 ± 281.4 µm2) in the nodose ganglion, and were medium to large in size in the dorsal root ganglion (Fig. 6C). Small neurons labeled with FB were not immunoreactive for TRPV2.

Fig. 4.

Fig. 4

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FB-labeled neurons relative to immunoreactivity for TRPV1 and TRPV2 in the jugular ganglion (JG) and nodose ganglion (NG) of five rats. (A) TRPV1 immunoreactivity was observed in 59.3% (70/118) and 10.7% (17/159) of FB-labeled neurons in the jugular and nodose ganglia, respectively. (B) TRPV2 immunoreactivity was observed in 8.8% (8/91) and 2.6% (5/191), respectively.

Fig. 5.

Fig. 5

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TRPV1 immunoreactivity in FB-labeled neurons in the jugular ganglion (JG; A), nodose ganglion (NG; B), and dorsal root ganglion at segmental level of C5 (C). Panels A-1 to C-1 represent the same areas as panel A-2 to C-2. (A) Some FB-labeled neurons are immunoreactive for TRPV1 (arrows) in the jugular ganglia. An FB-labeled and TRPV1-immunonegative neuron is also shown (arrowheads). (B) FB-labeled neurons are both TRPV1-immunoreactive (arrow) and TRPV1-negative (arrowheads) in the nodose ganglia. (C) Small to medium sized neurons immunoreactive (arrow) or negative (arrowhead) for TRPV1 in the dorsal root ganglion (C5). (D) Varied cell size of FB-labeled neurons immunoreactive for TRPV1 in the jugular ganglia from five rats. (E) Varied cell size of FB-labeled neurons in the nodose ganglia.

Fig. 6.

Fig. 6

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TRPV2 immunoreactivity in FB neurons in the jugular ganglion (JG; A), nodose ganglion (NG; B), and dorsal root ganglion at segmental level of C6 (C). Panels 1 in A-1 to C-1 represent the same area as panel A-2 to C-2. (A) FB-labeled neurons immunoreactive for TRPV2 (arrows) or negative for TRPV2 (arrowhead). (B) FB-labeled neurons either immunoreactive (arrows) or negative (arrowheads) for TRPV2 in the nodose ganglion. (C) Large neurons immunoreactive (arrow) or negative (arrowhead) for TRPV2 in the dorsal root ganglion (C6). (D) FB-labeled neurons immunoreactive for TRPV2 in the jugular ganglia; these are few in number and medium to large in size. (E) FB-labeled neurons immunoreactive for TRPV2 in the nodose ganglia; these are very few in number, and are medium to large in size.

Discussion

Distribution of TRPV1 and TRPV2 in nerve endings of the tracheobronchial tree

This study demonstrated a wide distribution of TRPV1-immunoreactive nerve endings throughout the lower respiratory tract of rats. These nerve endings could be nociceptors arising from nonmyelinated C or small myelinated Aδ fibers, which are activated by the TRPV1 activator, capsaicin (see review in Undem et al. 2002). Numerous intraepithelial nerves in rat contain neuropeptides (Baluk et al. 1992; Kusindarta et al. 2004), and the present study showed receptor channels for nociception distributed in intraepithelial free nerve endings. On the other hand, TRPV2 channels are opened by noxious heat in the TRPV2-expressing HEK293 cells (> 52 ºC; Caterina, 1999), or mechanical stretch and hyperosmolarity in vascular smooth muscle cells (Muraki et al. 2003). The subepithelial TRPV2-immunoreactive nerve fibers identified in this study might therefore play a role in nociception and/or perception of mechanical stress in the respiratory mucosa. Furthermore, TRPV2-immunoreactive nerve cells were observed in the intrinsic ganglia, implicating this channel type in modulating postganglionic neurons of the parasympathetic nerves in visceral organs. This is supported by the wide distribution of TRPV2 in visceral intrinsic neurons such as those in the gastrointestinal tract (Kashiba et al. 2004) and larynx (Yamamoto & Taniguchi, 2005).

Heterogeneity of tracheal nerve endings based on chemical characteristics

It has been suggested that airway nociceptors release several neuropeptides including SP and CGRP by axon reflex to induce neuroinflammatory events such as bronchoconstriction, extravasation, and mucus secretion (Barnes, 2001). Several TRPV1-immunoreactive nerve endings in this study colocalized with SP or CGRP, and such colocalization might be morphologically typical of the axon reflex. In the present study, the colocalization patterns could indicate heterogeneity in the tracheobronchial nociceptors. Based on the double staining for TRPV1 and SP, TRPV1-immunoreactive nerve endings could be further subclassified as SP-positive or SP-negative. Selected TRPV1-immunoreactive lung neurons in the dorsal root ganglia and jugular-nodose ganglia complex in mouse also showed SP immunoreactivity (Kollarik et al. 2003; Dinh et al. 2004; Undem et al. 2004). The double immunofluorescence for TRPV1 and CGRP in the present study revealed three subclasses of TRPV1-immunoreactive nerve endings: positive for both TRPV1 and CGRP, positive for TRPV1 and negative for CGRP, or negative for TRPV1 and positive for CGRP. In a previous study, lung-projected neurons in rat dorsal root ganglia and jugular-nodose ganglia complexes were classified into four subclasses according to binding patterns for lectin IB4, a marker of C-fiber neurons, and CGRP immunoreactivity: IB4+/CGRP+, IB4+/CGRP−, IB4−/CGRP+, and IB4−/CGRP− (Plato et al. 2006). On the other hand, Aδ and C fibers of rat dorsal root ganglia were classified into nine phenotypes based on electrophysiological and immunohistochemical analyses (Petruska et al. 2000a,2000b, 2002). In these reports, Aδ and C fibers contained nociceptors both sensitive and insensitive for capsaicin. Although the phenotypes of Aδ and C fibers in the airway are not fully characterized, capsaicin-sensitive and capsaicin-insensitive subclasses were also identified in the C fibers of mouse lung (Kollarik et al. 2003). Thus, it seems that non-nociceptive receptors immunoreactive for CGRP but not for TRPV1 exist in the airway mucosa. It follows that varying patterns of immunoreactivity for TRPV1 and neuropeptides such as SP and CGRP reflect the existence of phenotypically different Aδ- and C-fiber neurons projecting to the trachea.

Almost none of the TRPV2-immunoreactive nerve endings in the trachea was also immunoreactive for SP or CGRP in the present study. Some intraepithelial nerve endings immunoreactive for TRPV2 might thus represent a phenotype of nociceptors that do not contain SP or CGRP.

Origin of tracheal nerve endings containing TRPV1 and TRPV2

SP- and/or CGRP-immunoreactive neurons projecting to the trachea and larynx have been reported mainly in the jugular ganglion of guinea-pig (Kummer et al. 1992; Hunter & Undem, 1999) and rat (Springall et al. 1987). On the other hand, nociceptors in the lung arise from both jugular and nodose ganglia (Springall et al. 1987; Undem et al. 2004). The present study found that 10.7% of FB-labeled nodose ganglion neurons were also immunoreactive for TRPV1, indicating that some of the TRPV1-immunoreactive tracheal nerve endings originated from the nodose ganglion. As FB was injected into the lower parts of the trachea in the present study in contrast to previous reports (Kummer et al. 1992; Undem et al. 2004), TRPV1-immunoreactive nerve endings in the lower trachea might originate from both ganglia. In addition, FB-labeled and TRPV1-immunoreactive neurons in the jugular and nodose ganglia varied in size in the present study, suggesting that nociceptive vagal sensory neurons would also vary in size.

On the other hand, although tracheal TRPV2 nerves arise from both jugular and nodose ganglia as TRPV1 nerves, they are fewer in number. This suggests that only a small proportion of TRPV2-immunoreactive neurons in the jugular and nodose ganglia have a mechanosensory function.

Acknowledgments

This study was partly supported by a Grant-in-Aid from the JSPS, Japan (19658108).

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