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Systems Neurobiology Laboratory, Department of Neurobiology, University of California Los Angeles, Box 951763, Los Angeles, CA 90095, USA
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(Received 23 December 2003;
accepted after revision 8 January 2004;
first published online 14 January 2004)
Corresponding author C. Morgado-Valle: Department of Neurobiology, David Geffen School of Medicine at UCLA, Box 951763, Los Angeles, CA 90095-1763, USA. Email: cmorgado{at}mednet.ucla.edu
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Introduction |
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To investigate how disruption of endogenous SP release affects respiratory rhythm, we examined the effects of capsaicin, the pungent extract of cayenne pepper, on respiratory motor output in in vitro slices from neonatal rat. Capsaicin selectively and potently increases the spontaneous release of SP, calcitonin gene-related peptide, neuropeptide Y and neurokinin A (Dalsgaard et al. 1983; Hua et al. 1986; Go & Yaksh, 1987; Diez Guerra et al. 1988; Kar & Quirion, 1992; Zhao et al. 1992; Wimalawansa, 1993; Cuesta et al. 1999), as well as glutamate (Sorkin & McAdoo, 1993; Li & Eisenach, 2001), both in vitro and in vivo. Capsaicin acts by binding to presynaptic vanilloid receptors (VR1), opening a cationic channel (Caterina et al. 1997). mRNA for VR1 is expressed in primary sensory neurones, and in brain including cortex, hippocampus, striatum, locus coeruleus and inferior olive (Mezey et al. 2000). Systemic administration of capsaicin to adult rats produces a rapid, long-lasting fall in body temperature and changes in EEG activity in the anterior hypothalamus, medial habenula, substantia nigra, and dorsal raphe nucleus (Rabe et al. 1980). Microinjection of capsaicin into the substantia nigra enhances motor activity (Dawbarn et al. 1981) and into the commissural nucleus of the solitary tract reduces respiratory frequency and causes apnoea (Mazzone & Geraghty, 1999).
We examined capsaicin-induced changes in respiratory-related activity in a neonatal rat medullary slice preparation. Capsaicin significantly diminished respiratory-related motor output, which could be restored by subsequent application of SP. Capsaicin evoked a dose-dependent release of glutamate, as determined by a colorimetric method, and depletion of SP, as determined by immunohistochemistry. These results suggest that depletion of SP (and perhaps other neuropeptides) and glutamate in the slice preparation by capsaicin affects the respiratory rhythm generation kernel.
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Methods |
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Experiments were performed on neonatal rat transverse brainstem slices that generate respiratory motor output (Smith et al. 1991). All protocols were approved by the Office for the Protection of Research Subjects, University of California Research Committee. Sprague-Dawley neonatal rats (0–3 days old) were anaesthetized with isoflurane, decerebrated and the neuroaxis was isolated. The cerebellum was removed and the brainstem sectioned serially in transverse plane using a Vibratome (Technical Products International, VT 1000) until landmarks, e.g. nucleus ambiguus, inferior olive, at the rostral boundary of the preBötC were visible. A transverse slice (550 µm) containing the preBötC was cut. The dissection was performed in a standard artificial cerebrospinal fluid (ACSF) containing (mM): 128 NaCl, 3 KCl, 1.5 CaCl2, 1 MgSO4, 23.5 NaHCO3, 0.5 NaH2PO4 and 30 glucose, bubbled with 95% O2–5% CO2 at 27°C. The slice was transferred to a 1 ml recording chamber and anchored using a platinum frame and a grid of nylon fibres. The chamber was mounted to a fixed-stage microscope (Leica VM LFS-1) and perfused with ACSF (6 ml min-1).
Rhythmic respiratory-related motor output was recorded from the XIIn using fire-polished glass suction electrodes (A-M Systems, Inc.) and a differential amplifier (Grass Instruments, P5 series). To obtain a robust and stable rhythm, ACSF K+ concentration was elevated to 9 mM; slices were perfused for 50 min before any experimental manipulation. XIIn activity was rectified and integrated (
XIIn).
Drugs obtained from Sigma Chemical were bath applied at the following concentrations: 10–50 µM capsaicin, 10–500 nM SP, 50–300 µM dihydrokainic acid (DHK). The non-transportable glutamate transporter inhibitor DL-threo-ß-benzyloxyaspartate (TBOA) was obtained from Tocris (Ellisville, MO, USA).
Electrophysiological signals were acquired digitally at 4–20 kHz using pCLAMP software (Axon Instruments) after low-pass filtering. Igor Pro (Wave Metrics, Inc., OR, USA), Chart (ADInstruments) and Microsoft Excel were used for data analyses.
One-way analysis of variance (ANOVA) test was used to determine statistical differences of the mean values of variables. Student's paired t tests were used to compare results before and after capsaicin treatment. Results are expressed as mean ±S.E.M.
Glutamate release measurement
The concentration of glutamate released by capsaicin-treated slices was measured indirectly using a colorimetric assay (Taylor & Hewett, 2002). This method is based on the principle that glutamate is converted to 2-oxoglutarate via glutamate dehydrogenase (GDH) in the process of reducing NAD+ to NADH. The subsequent oxidation of NADH drives a reaction catalysed by diaphorase resulting in the conversion of p-iodonitrotetrazolium (p-INT) to a formazan product, the absorption of which is measured spectrophotometrically (490 nm).
To generate samples, brainstem slices were obtained as described above. Each slice was anchored in the bottom of a 24-well plate with a platinum frame and a grid of nylon fibres and incubated in 450 µl of 9 mM K+ ACSF bubbled with 95% O2–5% CO2 at 28°C during 30 min. Slices were then stimulated for 60 min with 800 µl of solution containing 10, 30 or 50 µM capsaicin, 0.1 mM TBOA and 0.3 mM DHK to block reuptake of released glutamate. Supernatant was collected and kept on ice. Control release was measured from slices treated with TBOA or DHK alone. To obtain a time course of capsaicin-evoked glutamate release, the same procedure was used, but 450 µl instead of 800 µl were applied during periods of 20 min. Samples were either stored at -20°C or analysed immediately. For analysis, 200 µl of each sample was boiled (95–100°C; 5 min) to inactivate enzymes that use NAD+ or NADH as cofactors. Samples were then allowed to cool to room temperature. Then 100 µl of reaction cocktail containing 96 mM triethanolamine-HCl, 3 mM K2HPO4, 6 mM NAD, 0.24 mM p-INT violet, 0.15% Triton X-100, 0.1 U µl-1 diaphorase and 29 U ml-1L-glutamic dehydrogenase was added (see Taylor & Hewett, 2002). The reaction was allowed to proceed at room temperature for 60 min while rocking. Next, 250 µl of each reaction mixture was transferred to a 96-well plate, and the absorbance at 490 nm was spectrophotometrically determined using a microtitre plate reader (Perkin-Elmer; Boston, MA, USA). The glutamate concentration in the experimental medium was calculated via linear regression (Igor Pro, WaveMetrics, Inc.) using known glutamate solutions as standards (0.75, 1.5, 3, 6, 12 and 24 µM). All standard solutions were treated identically to the samples, as described above. Data are expressed as mean ±S.E.M. of four independent determinations per group.
Anti-SP immunohistochemistry
Brainstem slices from newborn rats (1 day old) were obtained as described above and treated with 10 µM capsaicin until cessation of respiratory motor output. Control slices were perfused for 2 h with ACSF. Slices were then fixed in 4% paraformaldehyde in PBS, cryoprotected in 25% sucrose PBS, embedded in OCT compound tissue freezing medium, sectioned at 40 µm on a cryostat and processed. Sections were incubated in rabbit anti-SP (Immunostar) primary antibody diluted (1 : 800) in serum at 4°C overnight, placed in biotin conjugated species-specific secondary antibody (Vector Laboratories, Burlingame, CA, USA), stained using the ABC method (Vector Laboratories) and mounted on gelatin-subbed slides.
Quantification of SP immunoreactivity
For quantification of SP-like immunoreactive fibres, 40 µm sections at the level of the preBötC from control and treated slices were examined with light microscopy. Four images from different focal planes distributed through the depth of each section from a constant field (356 µm x 264 µm) ventrolateral to nucleus ambiguus were obtained using the Neofluar x 40 objective of an Axioplan 2 microscope fitted with an AxioCam HRm (2/3' sensor) on a x 0.63 video coupler. The magnification of fibres measured on the computer screen was x 989, calculated using the formula: Total magnification = objective mag. x video coupler mag. x video mag. The video magnification was calculated dividing the actual image diagonal (as measured on the screen) by the CCD chip diagonal (Diagnostic Instruments, Inc., www.diaginc.com).
Images were superimposed using Adobe Illustrator software (Adobe Systems Incorporated, CA, USA). The length of SP-like immunoreactive fibres was measured by tracing with the ‘measure length tool’ in AxioVisio4 software (Carl Zeiss, Germany) the immunostained fibres. The length values for all fibres obtained from each side of a section were added; the values are expressed as total length of immunoreactive fibres per side (Kinkelin et al. 2000). Data are expressed as the mean ±S.E.M.
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Results |
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Bath application of capsaicin decreased the frequency of XIIn output in a dose- and time-dependent manner. The respiratory period of untreated slices was initially 5.6 ± 0.1 s, and after 180 min 12.2 ± 0.7 s (n= 4). Bath application of 10 µM capsaicin slowed respiratory rhythm frequency after 60 min of perfusion, followed by a sudden cessation of respiratory rhythm after 100–150 min (n= 10; Fig. 1A). At 30 µM capsaicin caused rhythm cessation after 90–110 min (n= 4) and 50 µM capsaicin caused rhythm cessation after 55–60 min (n= 4; Fig. 1A). To compare the effects of capsaicin on peak amplitude, area and burst duration of the integrated XIIn activity (XIIn) we averaged five control bursts before capsaicin application and the last five before rhythm cessation. XIIn peak amplitude remained stable during 10 µM capsaicin application but decreased 21 and 49% during application of 30 and 50 µM capsaicin, respectively (P < 0.05, Fig. 1 and Table 1). Compared to control, 10 µM capsaicin produced a 44% reduction of burst area (P < 0.05), 30 µM caused a 56% reduction (P < 0.05) and 50 µM reduced burst area by 71% (P < 0.01). 10 µM capsaicin produced a reduction of XIIn burst duration from 0.62 ± 0.06 to 0.38 ± 0.03 s (P < 0.05). 30 µM capsaicin caused a reduction of burst duration from 0.61 ± 0.05 to 0.23 ± 0.01 s (P < 0.01), and 50 µM capsaicin reduced the burst duration from 0.59 ± 0.03 to 0.21 ± 0.02 s (P < 0.01).
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Glutamate release in response to capsaicin was measured from slices treated with 100 µM TBOA + 300 µM DHK (to block glutamate uptake). Incubation of these slices with capsaicin resulted in a concentration-dependent release of glutamate significantly greater than in slices treated with uptake inhibitors alone. In slices stimulated for 60 min with 10 µM capsaicin (n= 4), glutamate release increased to 3.1 ± 0.9 times that without capsaicin. Similarly, 30 µM (n= 4) and 50 µM (n= 4) capsaicin increased glutamate release 4.1 ± 0.1- and 7.7 ± 0.5-fold, respectively (Fig. 2A).
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SP-like fibre immunoreactivity depletion in and around preBötC
The adult rat medulla has a high content of SP-like immunoreactive fibres and varicosities descending ventrolaterally from the nucleus tractus solitarius to surround motoneurones of the nucleus ambiguus and neurones in the preBötC (data not shown). Based on this observation, we used slices treated with 10 µM capsaicin for 2 h for immunohistochemistry studies. Motoneurones from the nucleus ambiguus are easily identified as a compact group of large (30–40 µm) cells, with preBötC neurones ventrolateral to these motoneurones (Gray et al. 1999; Guyenet et al. 2002). Sections cut from control slices showed SP-like immunoreactive fibres and varicosities descending in the same pattern as in adult rats. Sections cut from slices treated with 10 µM capsaicin for 120 min (the time necessary to stop rhythm) showed qualitatively less SP-like immunoreactive fibres than control slices in the area surrounding nucleus ambiguus, readily discernible by visual inspection. To quantify these differences, the length of SP-like immunoreactive fibres contained in a field ventrolateral to the nucleus ambiguus approximating the location of the preBötC (see Methods) was measured (Fig. 3). The total length of immunoreactive fibres per side in sections from capsaicin-treated slices was reduced by 57% relative to control sections (348 ± 10 µm and 807 ± 37 µm, respectively, n= 12 control and 24 treated sections from 3 independent experiments for each group, P < 0.01).
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After cessation of respiratory motor output caused by 10 µM capsaicin, bath application of SP restored rhythmic activity. At 10 nM, SP re-established a respiratory rhythm similar to the control rhythm (n= 6; Fig. 4A). However, peak XIIn, area, burst duration and period were significantly different from control values (P < 0.05 for amplitude and period, P < 0.01 for area and burst duration; Fig. 4B). Rhythmic activity restarted 
3 min after bath application of SP and persisted as long as SP remained in the bath. Rhythmic motor output ceased within a few minutes after SP was completely washed out from the recording chamber. Slices treated with 30 µM capsaicin required 500 nM SP to re-establish respiratory rhythm (n= 3).
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XIIn had a significantly smaller amplitude and burst duration (P < 0.05) and period (P < 0.01) and a larger area (P < 0.05) than control XIIn (Fig. 4D). In slices treated with 10 µM capsaicin, bath application of ACSF containing [K+] from > 9–13 mM produced an increase of tonic activity but failed to restore respiratory activity (n= 3, data not shown).
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Discussion |
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The preBötC is a limited portion of the ventrolateral respiratory column characterized by a concentration of neurones expressing NK1R (Gray et al. 1999; Guyenet et al. 2002) for which SP is the endogenous ligand (Harrison & Geppetti, 2001). The precise role of SP in respiratory rhythm generation or modulation is not known. Exogenously applied SP enhances respiratory activity in vivo (Euler & Pernow, 1956) and in vitro (Yamamoto et al. 1992; Gray et al. 1999; Shvarev et al. 2002). In vivo injection or topical application of [D-Pro2, D-Trp7,9]-SP, a NK1R antagonist, within the adult rat ventrolateral medulla decreases ventilation (Chen et al. 1988). However, transgenic mice lacking the preprotachykinin gene (which encodes for the precursor of SP) or the NK1R gene show an almost normal breathing pattern (Ptak et al. 2000; Telgkamp et al. 2002), suggesting that the activation of the SP signal transduction pathway can modulate respiratory pattern but is either not essential for rhythm generation or is essential and in transgenic mice compensatory mechanisms are present.
In slices from normal neonatal CD-1 mice, antagonism of NK1R with spantide results in irregular respiratory activity and a decreased frequency (Telgkamp et al. 2002). In contrast, other authors have observed no effects in respiratory frequency after SP antagonist application to en bloc preparations (Yamamoto et al. 1992; Monteau et al. 1996). This discrepancy may be attributed to the differences between slice and en bloc preparations (Mellen et al. 2003).
Whether NK1Rs are activated by endogenous SP release under physiological conditions is not known. Inhibition of enzymatic degradation of endogenous SP with a peptidase inhibitor mixture does not affect respiratory frequency in en bloc preparations (Ptak et al. 1999). This suggests that the endogenous release of SP is sufficiently low so that an increase induced by reducing degradation still leaves the SP concentration too low to affect rhythm. Consistent with our results is the possibility that under control conditions a very low concentration (in the pico- or femptomolar range) of SP trickles out of the synapse and permits a critical process for rhythmogenesis, but that this concentration is too low to otherwise affect neuronal excitability.
A dense network of SP-immunoreactive fibres and varicosities surround nucleus ambiguus (Holtman, 1988) and preBötC neurones (authors' unpublished observations). Capsaicin induced a decrease in SP-like immunoreactivity in fibres penetrating those nuclei; a similar decrease of SP immunoreactivity is observed in the brainstem and respiratory tract after treatment with capsaicin in vivo (Ramirez-Romero et al. 2000; Kyrkanides et al. 2002) and in dorsal root ganglion neurones in vitro (Jeftinija et al. 1992). The nucleus tractus solitarii, which contributes to the ventilatory response to hypoxia, possesses a high content of neuropeptides, with SP being the most abundant (Ljungdahl et al. 1978; Maley & Elde, 1982; Maley, 1996), and is suggested as the source of the SP-containing fibres in the ventrolateral medulla (Loewy & Burton, 1978; Bystrzycka, 1980; Agassandian et al. 2002). Other potential sources of SP include the raphe obscurus and the parapyramidal region, areas that project to the ventral respiratory group (Holtman & Speck, 1994) and are present in our slice.
Capsaicin potently and selectively causes release of SP and other neuropeptides such as calcitonin gene-related peptide, neuropeptide Y and neurokinin A from presynaptic terminals both in vitro and in vivo (Diez Guerra et al. 1988; Donnerer & Amann, 1992; Kar & Quirion, 1992). As supported by our immunohistochemistry results, capsaicin depleted SP from fibres in and around the preBötC, presumably contributing to the cessation of rhythm. Once the respiratory rhythm ceased, bath application of nanomolar levels of SP restored rhythmic activity in XIIn motor output and necessarily in preBötC neurones. Our results are consistent with the following sequence of events: (i) SP and perhaps other peptides are released tonically at low levels and are permissive for one or more key processes underlying rhythmogenesis; (ii) capsaicin depletes SP and other peptides, disabling this key process and leading to cessation of rhythm, and; (iii) exogenous application of SP either restores this key process and/or increases neuronal excitability in NK1R expressing neurones, i.e. preBötC neurones, sufficiently to re-establish rhythmic activity.
The lack of NK1R in transgenic mice does not affect the resting respiratory activity compared to wild-type mice but is associated with a weaker hypoxic ventilatory response in adults (Ptak et al. 2002). Similarly, pretreatment of rats with CP-96345, a potent non-peptide NK1R antagonist, results in a dose-dependent decrease of the hypoxic ventilatory response (De Sanctis et al. 1994) by reducing the change in respiratory frequency. Depletion of SP in adult rats, by neonatal exposure to capsaicin, markedly reduces the ventilatory response to hypoxia (De Sanctis et al. 1991). The absence of SP in mice lacking the preprotachykinin gene leads to a significantly altered respiratory response during anoxia (Telgkamp et al. 2002). These effects could result from changes in the preBötC, as destruction of preBötC NK1R-expressing neurones produces pathological responses to hypoxia (Gray et al. 2001). Our results suggest SP could also play an important role in maintaining respiratory activity during normoxia, though not necessarily by the signalling pathways involved in modulation of respiratory pattern.
In addition to depleting SP (Juranek & Lembeck, 1997; Cuesta et al. 1999; Ramirez-Romero et al. 2000; Afrah et al. 2001), capsaicin can modulate glutamatergic transmission at primary afferent synapses in the spinal dorsal horn (Urban et al. 1985), visceral ganglia (Bielefeldt, 2000), locus coeruleus (Marinelli et al. 2002) and spinal cord (Ueda et al. 1994; Juranek & Lembeck, 1997; Li & Eisenach, 2001). In our endogenously active slice preparation, capsaicin produced a dose- and time-dependent increase of glutamate accumulation in the supernatant. Whether glutamate was released as a direct result of the effect of capsaicin on presynaptic terminals or indirectly by increased activity resulting from the activation of NK1Rs by the SP released remains to be elucidated. Following application of capsaicin we did not observe a transient increase in respiratory frequency, presumably because glial and neuronal glutamate transporters are very efficient at removing any excess of glutamate from the synapse preventing receptor desensitization (authors' unpublished observations). The capsaicin-evoked reduction of respiratory frequency and ultimate cessation of respiratory-related motor output activity could be due to the depletion of glutamate from terminals synapsing onto preBötC neurones. However, substantial glutamate depletion as the principal mechanism for rhythm cessation is inconsistent with our results, since SP alone restores the rhythm. If glutamate was completely depleted within the preBötC by capsaicin, it is not obvious how this could occur.
Nonetheless, blockade of glutamate uptake rapidly restored respiratory rhythm that had ceased following exposure to 150 min of 10 µM capsaicin. We suggest the following sequence of events: (i) capsaicin induced low levels (too low to noticeably change respiratory motor output) of tonic glutamate release; (ii) when integrated over 100–150 min the tonic release of glutamate resulted in partial depletion of releasable glutamate; (iii) the reduced amounts of glutamate available for release did not reach the concentration necessary for rhythmicity, and (iv) blockade of transporters allowed glutamate accumulation sufficient to restore rhythm. At higher concentrations of capsaicin some other effects beside SP and glutamate depletion may also contribute to the cessation of the respiratory rhythm since: (i) rhythm ceased rapidly, and (ii) SP or glutamate uptake inhibition failed to restore rhythmic activity. Moreover, our results do not exclude the possibility that capsaicin may be depleting other neuromodulators that, like SP, may coexist with glutamate in presynaptic terminals.
In conclusion, the effect of depletion of SP and perhaps other peptides from presynaptic terminals by capsaicin slows and ultimate stops the respiratory rhythmic motor output in rat medullary slices. We propose that this occurs within the preBötzinger complex, where NK1R and glutamate receptors coexist.
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