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Am J Physiol Regul Integr Comp Physiol 279: R1215-R1223, 2000;
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Vol. 279, Issue 4, R1215-R1223, October 2000

Substance P in the nucleus of the solitary tract augments bronchopulmonary C fiber reflex output

T. Mutoh1,2, A. C. Bonham1, and J. P. Joad2

1 Departments of Internal Medicine and Pharmacology and 2 Department of Pediatrics, University of California, Davis, Sacramento, California 95616


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Bronchopulmonary C fibers defend the lungs against injury from inhaled agents by a central nervous system reflex consisting of apnea, cough, bronchoconstriction, hypotension, and bradycardia. Glutamate is the putative neurotransmitter at the first central synapses in the nucleus of the solitary tract (NTS), but substance P, also released in the NTS, may modulate the transmission. To test the hypothesis that substance P in the NTS augments bronchopulmonary C fiber input and hence reflex output, we stimulated the C fibers with left atrial capsaicin (LA CAP) injections and compared the changes in phrenic nerve discharge, tracheal pressure (TP), arterial blood pressure (ABP), and heart rate (HR) in guinea pigs before and after substance P injections (200 µM, 25 nl) in the NTS. Substance P significantly augmented LA CAP-evoked increases in expiratory time by 10-fold and increases in TP and decreases in ABP and HR by threefold, effects prevented by neurokinin-1 (NK1) receptor antagonism. Thus substance P acting at NTS NK1 receptors can exaggerate bronchopulmonary C fiber reflex output. Because substance P synthesis in vagal airway C fibers may be enhanced in pathological conditions such as allergic asthma, the findings may help explain some of the associated respiratory symptoms including cough and bronchoconstriction.

neuropeptide; tachykinins; guinea pigs; respiratory reflexes


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

STIMULATION OF THE NONMYELINATED vagal sensory afferent C fibers in the lungs and airways, collectively termed the bronchopulmonary C fibers, elicits a central nervous system (CNS) and a local axon reflex. Both reflexes are thought to protect the lungs from further injury from inhaled agents (14). The CNS reflex is a highly coordinated response, including an expiratory apnea, rapid shallow breathing, cough, bronchoconstriction, increased mucous secretion, hypotension, and bradycardia (14). The axon-reflex response, local to the airways, includes bronchoconstriction, local inflammation, and increased mucus secretion (36). The bronchopulmonary C fiber sensory endings are activated by various stimuli, including ozone (16), cigarette smoke (34), changes in airway surface osmolarity (46), release of local autocoids (13, 15), and mechanical perturbations associated with acute pulmonary edema (13). The primary afferent fibers make their first central synapse in the caudomedial nucleus of the solitary tract (NTS) (6).

The excitatory neurotransmitter at these NTS synapses is most likely glutamate. The excitatory amino acid is synthesized in the nodose and jugular ganglia, transported centrally, and released in the NTS by vagal afferent fibers (33, 41). In addition, glutamate has been shown to specifically mediate synaptic transmission between primary afferent bronchopulmonary C fibers and the second-order NTS neurons (54). The neuropeptide substance P is also synthesized in the nodose and jugular ganglia and has been shown to be transported peripherally (8) and released locally in the airways (36). A number of studies have implicated the release of substance P in the airways in allergen-induced asthma (22, 36). The physiological relevance of substance P actions in the central bronchopulmonary C fiber reflex pathway is less clear. However, there is considerable morphological and physiological evidence suggesting that substance P is released at central synapses in the NTS. First, this NTS region contains a high density of substance P-containing nerve terminals (8, 23, 24, 27, 30, 31, 37, 52), some of which have been shown to emanate from vagal afferent fibers, in particular, capsaicin-sensitive afferent C fibers (26, 48), as well as from axons and soma throughout the CNS (18). Secondly, there is a parallel distribution of substance P (neurokinin-1, NK1) receptors with respect to the nerve terminals, providing proximal targets for substance P release in the nucleus (4, 20, 28, 40). Thirdly, iontophoretic application of substance P (19, 29, 42, 55) or selective NK1 receptor agonists (38) on NTS neurons has been found, in most studies, to have an excitatory effect, suggesting that there are functional NK1 receptors on NTS neurons. Finally, microinjections of substance P or capsaicin [which releases tachykinins, including substance P (9)] in the NTS have also been shown to evoke respiratory changes, which are largely, but not exclusively, a slowing of respiratory rate or apnea (5, 11, 39). Because these respiratory changes could be elicited by activation of neurons receiving input from the baroreceptors, laryngeal receptors, slowly adapting pulmonary stretch receptors, and bronchopulmonary C fiber receptors, the extent to which substance P specifically interacts with the bronchopulmonary C fiber afferent pathway is not clear. Thus the purpose of this study was to specifically examine the contribution of substance P at NTS synapses on the bronchopulmonary C fiber reflex responses. We hypothesized that if substance P has an excitatory effect at NTS synapses in the bronchopulmonary C fiber afferent pathway, then exogenous application of the neuropeptide should augment the NTS neuronal responses to bronchopulmonary C fiber input and ultimately lead to an increase in at least some component of the reflex output. To test this hypothesis, we determined the effects of microinjections of substance P before and after NK1 receptor blockade in the caudomedial NTS on components of bronchopulmonary C fiber reflex output: phrenic nerve discharge (as an index of neural respiratory rate), tracheal pressure (TP), arterial blood pressure (ABP), and heart rate (HR). We stimulated the bronchopulmonary C fibers with left atrial injections of the C fiber stimulant, capsaicin (14).


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

All experimental protocols in this work were reviewed and approved by the Institutional Animal Care and Use Committee in compliance with the Animal Welfare Act and in accordance with Public Health Service policy on humane care and use of laboratory animals.

General animal preparation. Male Dunkin-Hartley guinea pigs (n = 12, Charles River Laboratories, Raleigh, NC) were anesthetized with an injection of urethan (1.6 g/kg ip) and then given supplemental doses of pentobarbital sodium (4 mg/kg iv) about every hour as needed. Before neuromuscular blockade, adequacy of anesthesia was determined every 30 min by pinching the hindlimb paw and monitoring for hindlimb flinch or withdrawal or sudden fluctuation of ABP (>5 mmHg) or HR (>10%). During neuromuscular blockade, adequacy of anesthesia was tested every half-hour by determining if there was a spontaneous or paw pinch-evoked fluctuation or increase (>5 mmHg) in ABP or increase (>10%) in HR. Each guinea pig was placed on a servocontrolled water blanket, and body temperature was monitored via a rectal temperature probe and maintained within 37 ± 1°C. Catheters were introduced into the jugular vein for administering fluids and drugs and into the carotid artery for monitoring ABP and withdrawing samples for arterial blood gases. The trachea was cannulated, and a catheter was connected to a side port of the endotracheal tube to monitor TP. Each guinea pig was prepared with bilateral pneumothoraces by incisions made in the chest wall and mechanically ventilated with oxygen-enriched humidified air with a tidal volume of 8 ml/kg. The ventilator rate was set initially at 35-40 breaths/min, and the positive end-expiratory pressure was set at 2 cmH2O. Arterial blood gases and pH were maintained so that the pH was between 7.30 and 7.40 and the arterial PCO2 was between 35 and 45 Torr by adjusting ventilator rate and by infusing sodium bicarbonate. After tracheal intubation, each animal was paralyzed with gallamine triethiodide (3 mg/kg iv) every hour as needed. The pericardium was opened, and a cannula (0.58-mm ID) prefilled with capsaicin (2.5 µg/ml) was inserted into the left atrium through the left atrial appendage. Both cervical vagus nerves were separated from the carotid artery and sectioned below the diaphragm to eliminate afferent traffic from vagally innervated viscera below the diaphragm. The aortic depressor nerves were carefully separated from the vagus nerves and cut bilaterally to eliminate aortic baroreceptor input. The fourth cervical (C4) branch of the left phrenic nerve was isolated in the neck and cut distally. For recording neural respiratory rate and expiratory time (TE), the central end of the phrenic nerve was placed on a bipolar silver hook electrode and covered with a mixture of warm petroleum jelly and mineral oil.

For microinjection of neuroactive substances into the NTS, the animal was placed in a stereotaxic frame. An occipital craniotomy was performed, and the caudal portion of the fourth ventricle was exposed by removing the dura mater and arachnoid membranes. A vertebral clamp was placed on the T2 spinal process to stabilize the brain stem.

Phrenic nerve activity was fed via a high-impedance source follower to second-stage amplifiers, filtered (0.3-3 kHz), and fed parallel to an oscilloscope, thermal chart recorder, audio monitor, and a digital tape recorder with a sampling rate of 11 kHz per channel for off-line analysis. TP, ABP, and HR were recorded through a Modular Instruments data-acquisition system (model M100, Malvern, PA).

Activation of the bronchopulmonary C fiber reflex. As in previous studies, the bronchopulmonary C fibers were stimulated by left atrial injections of capsaicin (LA CAP; 0.5 µg/kg) (43, 44). The reflex responses measured were TE (the interval between phrenic nerve bursts), TP, ABP, and HR. We have previously shown that this dose of capsaicin produces modest increases in individual primary bronchopulmonary C fiber impulse activity (<15% increase in baseline activity) (43), in bronchopulmonary C fiber-activated neuronal activity in the NTS (44), and in the corresponding reflex output, including a prolonged TE, increase in TP, and decreases in ABP and HR (44).

Microinjection procedures. Injections were made with the use of a multibarrel glass pipette (outside tip diameter 50.4 ± 3.2 µm, range 25-65 µm). Each barrel contained substance P, the NK1 receptor antagonist, CP-96345, the inactive enantiomer, CP-96344, or 2% Pontamine blue dye. The pipette was positioned in the NTS under visual guidance with the use of a microscope. On the basis of our previous experience in studying bronchopulmonary C fiber neurons in the NTS (6, 44, 54), we set the target coordinates in the caudomedial NTS as 0 to 300 µm rostral to the calamus scriptorius, 0 to 200 µm lateral to midline, and 400 to 600 µm ventral to the dorsal surface of the medulla. Injections (25 or 50 nl) were made bilaterally over a period of <5 s by applying pulses of pressurized nitrogen to each barrel with the use of a custom-constructed pressure injection system (6, 7). The volume of drug delivered was controlled by changing the injection pressure (7-12 cmH2O) and/or duration of the pressure pulse. The volume of the injection was directly monitored by viewing the movement of fluid meniscus in individual barrels of known diameter (0.58-mm ID) with the use of a microscope equipped with a calibrated eyepiece micrometer.

On the basis of previous studies in rats (5) and on pilot studies in guinea pigs, we selected a dose of substance P (200 µM, 25 nl) that had a threshold effect (<15% change from baseline values) on TE, TP, ABP, or HR. From additional pilot experiments, we determined that 1 mM (50 nl) of the high-affinity NK1 receptor antagonist CP-96345 (50) was necessary to either significantly attenuate or abolish the substance P-induced augmentation of the LA CAP-evoked reflex responses.

Experimental protocol. Data collected included TE (as an index of the respiratory component of the C fiber reflex output), TP (as a global index of airway tone), and the cardiovascular indices of ABP and HR.

After 2 min of recording to establish baseline values for TE, TP, ABP, and HR, capsaicin (0.5 µg/kg) was injected into the left atrium, and the changes in those parameters were measured. After a 30-min interval, substance P (200 µM, 25 nl) was injected bilaterally in the NTS. In all experiments, the pipette was initially placed on the right side of the NTS, then moved to the left side. After the second substance P injection, the LA CAP injection was repeated. After a 30-min interval, either the NK1 receptor antagonist CP-96345 or its inactive (2R,3R) enantiomer (CP-96344) (1 mM, 50 nl) was injected bilaterally in the NTS from an adjacent barrel before substance P injection. The time lag between the NK1 receptor antagonist (or its enantiomer) and the subsequent substance P injections was <10 s. Then the LA CAP injection was repeated. All animals received injections of the NK1 receptor antagonist and the inactive enantiomer. The injections were separated by 30 min, and the order was randomized. Six animals were administered CP-96345 first, followed by CP-96344; the sequence was reversed in four animals. There were no statistically significant differences in LA CAP-evoked changes in TE, TP, ABP, and HR on the basis of the order of injection (P > 0.05, unpaired t-test).

To evaluate recovery of the response to capsaicin, the LA CAP injection was repeated starting in 30-min intervals. Animals were killed after the experiment by a lethal dose injection of pentobarbital sodium.

Histology. Injection sites were marked by depositing the dye through a pipette adjacent to the pipette used for injecting the neuroactive agents without moving the pipette array from the injection site. Dye was deposited either by iontophoretic injection by passing current (10 µA for 7 s every 14 s for 15 min; electrode negative) or by pressure injection (50 nl). After euthanasia, the brain stem was removed and fixed in 4% paraformaldehyde and 10% sucrose. The brain stems were cut in 40-µm coronal sections and counterstained with Neutral Red. Recording sites were reconstructed from dye spots with the aid of a camera lucida drawing tube.

Pharmacological agents. A stock solution of capsaicin (1 × 10-2 M; Sigma Chemical, St. Louis, MO) was prepared in a vehicle (10% Tween 80, 10% ethanol, and 80% saline), and the desired concentration was prepared from concentrated stock solutions on the day of the experiment by dilution in saline. Substance P (200 µM; RBI, Natick, MA), the nonpeptide NK1-selective substance P antagonist (2S,3S)- cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)methyl)-1- azabicyclo[2.2.2]octan-3-amine (1 mM; CP-96345, Pfizer, Groton, CT) and its (2R,3R) enantiomer (1 mM; CP-96344, Pfizer) were prepared with each desired concentration by dilution in saline and were stored frozen (-80°C). All solutions were adjusted to a pH of 7.2-7.5.

Data analysis. Data collected included the capsaicin-evoked changes in TE, TP, ABP, and HR. The respiratory (phrenic nerve activity) response to capsaicin was determined by the ratio of the peak TE after the capsaicin injection to the mean TE averaged over the 2-min control period just before the capsaicin injection (TE peak/TE control). The peak increase in TP and the peak decrease in ABP or HR were defined as the 5-s bin with the biggest change within the initial 30 s after LA CAP compared with the control values averaged over 2 min before the capsaicin injection.

To determine whether the capsaicin-evoked changes (Delta ) from the averaged baseline values (taken after the NTS microinjections of substance P) to the peak responses for TE peak/TE control, TP, ABP, and HR were significantly different among the trials, a one-way ANOVA was used with treatment (LA CAP alone vs. substance P + LA CAP vs. CP-96345 + substance P + LA CAP vs. CP-96344 + substance P + LA CAP) as a within-subjects effect followed by a series of Fisher's contrast tests between the treatment groups after significant F tests.

As a secondary analysis, we also determined whether the capsaicin-evoked peak change in TE, TP, ABP, or HR under control conditions was significantly different from baseline by using a paired t-test. Finally, we determined whether NTS injections of substance P, CP-96345, or CP-96344 had an effect on TE, TP, ABP, or HR by using a paired t-test. Statistical significance was claimed when the probability of a type I error was <0.05.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

At the commencement of the experiments, the weights and arterial blood gases of guinea pigs were (mean ± SD) 472 ± 9 g; the PO2 was 395 ± 8 Torr; the PCO2 was 40.2 ± 1.3 Torr; and the pH was 7.35 ± 0.01.

Microinjection sites of substance P were marked with dye (n = 12) and histologically verified. All sites were located in the intermediate and caudal NTS and medial to the tractus, the region previously shown to contain bronchopulmonary C fiber afferent terminals (6, 32, 44, 54). Figure 1 shows a photograph of an example of a dye spot marking the pipette location site in the NTS in a coronal slice (Fig. 1A) and a composite of the reconstructed injection sites (Fig. 1B). The sites were centered between 650 and 1,000 µm caudal to the obex. In the guinea pig, the distance between the obex and the calamus scriptorius is ~1,000 µm. Thus this region corresponds to between 0 and 300 µm rostral to the calamus scriptorius. Within this circumscribed region of the NTS, there were no detectable site-dependent differences in the efficacy of the substance P injections.


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  		Fig. 1.   Substance P (SP) microinjection sites in the nucleus of the solitary tract (NTS). A: photomicrograph of a dye spot in a representative animal. B: composite of histologically verified microinjection sites in guinea pigs. * Recording site in A in composite. The injection sites were located from ~650 to 1,000 µm caudal to the obex and medial to the tractus solitarius. AP, area postrema; ts, tractus solitarius; C, central canal; and X, dorsal motor nucleus of the vagus. Calibration bar is for A and B.

Effect of substance P on bronchopulmonary C fiber reflex responses. As shown in the example in Fig. 2A, LA CAP injection slightly prolonged TE. Bilateral injection of substance P (200 µM, 25 nl) into the NTS enhanced the LA CAP-evoked prolongation of TE (Fig. 2B). The augmentation was abolished by prior bilateral injection of the NK1 receptor antagonist CP-96345 through an adjacent barrel in the NTS (Fig. 2C) but not by bilateral injection of the same volume of the inactive enantiomer CP-96344 (Fig. 2D).


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  		Fig. 2.   Example showing the effects of left atrial capsaicin (LA CAP) injection on phrenic nerve activity (PNA) and tracheal pressure (TP). A: under control conditions; B: after bilateral NTS microinjection of SP; C: after bilateral NTS microinjection of the neurokinin-1 (NK1) receptor antagonist CP-96345 and SP; and D: after bilateral NTS microinjection of CP-96344, the inactive enantiomer of the antagonist, and SP. The near-threshold effect of LA CAP on expiratory time (TE) was augmented by SP, an effect that was abolished by CP-96345 but not by CP-96344.

The grouped data are shown in Fig. 3. LA CAP produced a modest but statistically significant prolongation (13%) of TE over the baseline TE (P = 0.02, paired t-test). Bilateral substance P injections into the NTS, although having no effect on baseline TE (P > 0.05, paired t-test), augmented the capsaicin-evoked responses by 10-fold (LA CAP alone vs. substance P + LA CAP; P < 0.0001, Fisher's test). Prior bilateral injections of the NK1 receptor antagonist into the NTS, although having no effect on baseline TE (P > 0.05, paired t-test), abolished the augmentation by substance P (substance P + LA CAP vs. CP-96345 + substance P + LA CAP; P < 0.0001, Fisher's test). Bilateral injection of the inactive enantiomer had no effect on the substance P-induced augmentation (substance P + LA CAP vs. CP-96344 + substance P + LA CAP; P = 0.99, Fisher's test). The inactive enantiomer also had no effect on baseline TE (P > 0.05, paired t-test).


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  		Fig. 3.   Grouped data showing the peak of the effect of SP on LA CAP-evoked prolongation of TE (n = 12). LA CAP produced a slight increase in TE that was significantly augmented by bilateral NTS injections of SP (LA CAP vs. SP + LA CAP; P < 0.0001, Fisher's test). The augmented effects of SP were prevented by prior injection of the NK1 receptor antagonist CP-96345 (SP + LA CAP vs. CP-96345 + SP + LA CAP; P < 0.0001, Fisher's test) but not by the inactive enantiomer CP-96344 (SP + LA CAP vs. CP-96344 + SP + LA CAP; P = 0.99, Fisher's test). * P < 0.05.

The grouped data showing the time course of the evoked changes in TE are shown in Fig. 4. Under control conditions, LA CAP evoked the slightly prolonged TE within 1 breath after the injection. The onset latency averaged 1.5 ± 1.0 s and was not changed by any NTS injections. After bilateral substance P injections (Fig. 4B), LA CAP evoked a robust increase in TE that peaked in the first breath. The peak increase in TE waned after 2 breaths but remained elevated for ~15 breaths, when it returned to within 15% of baseline. When CP-96345 was injected before substance P (Fig. 4C), the contour of the threshold increase in TE was the same as when LA CAP was injected under control conditions. When CP-96344 was injected before substance P (Fig. 4D), the amplitude and time course of the LA CAP-evoked increase in TE were the same as when substance P was injected before the LA CAP.


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  		Fig. 4.   Time course showing the onset, amplitude, and duration of the changes in TE for the grouped data. A: LA CAP evoked a rapid-onset, small increase in TE within the first breath. B: after bilateral NTS injections of SP, LA CAP evoked an augmented increase in TE that peaked in the first breath and then returned to within 15% of baseline TE within 15 breaths. C: when CP-96345 injections preceded the SP injections, the shape of the LA CAP-evoked response was the same as in A. D: when CP-96344 injections preceded the SP injections, the onset, amplitude, and time course was the same as in B. Bar, second of the bilateral NTS SP injections. Time 0, LA CAP injection.

The grouped data showing the effect of substance P on the LA CAP-evoked TP, ABP, and HR responses are summarized in Fig. 5. Although the trend toward capsaicin-evoked changes in these cardiopulmonary responses from the baseline values did not reach statistical significance (P > 0.05 for all responses), the changes were significantly augmented by prior bilateral NTS substance P injections (LA CAP alone vs. substance P + LA CAP; P < 0.02 for all responses, Fisher's test). The substance P-induced augmentations of the TP, ABP, and HR responses were abolished by prior injection of the NK1 receptor antagonist (substance P + LA CAP vs. CP-96345 + substance P + LA CAP; P < 0.02 for all responses, Fisher's test) but not by injection of the inactive enantiomer (substance P + LA CAP vs. CP-96344 + substance P + LA CAP; P > 0.49 for all responses, Fisher's test). Microinjection of substance P, CP-96345, or CP-96344 did not alter the baseline TP, ABP, or HR (P > 0.05, paired t-test).


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  		Fig. 5.   Grouped data showing the peak of the effect of SP on the LA CAP-evoked decrease in arterial blood pressure (ABP; A), decrease in heart rate (HR; B), and increase in tracheal pressure (TP; C). LA CAP evoked small changes in TP, ABP, or HR that were not statistically significant. After bilateral NTS injections of SP, the LA CAP-evoked change in each parameter was significantly increased (LA CAP vs. SP + LA CAP; P < 0.02 for all responses, Fisher's test). The augmented effects of SP were prevented by prior injection of the NK1 receptor antagonist CP-96345 (SP + LA CAP vs. CP-96345 + SP + LA CAP; P < 0.02 for all responses, Fisher's test) but not by the inactive enantiomer CP-96344 (SP + LA CAP vs. CP-96344 + SP + LA CAP; P > 0.49 for all responses, Fisher's test). * P < 0.05.

The responses of TE, TP, and ABP to LA CAP recovered to the control response at an interval of 30 min after the last NK1 receptor antagonist or the enantiomer injection protocol (LA CAP alone vs. LA CAP recovery; P > 0.05, Fisher's test for all responses) (data not shown).


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The major finding of this study was that near-threshold changes in TE, evoked by stimulation of the bronchopulmonary C fibers, were augmented 10-fold by prior injections of substance P in the caudomedial NTS where the bronchopulmonary C fibers make their first central synapses (6, 32, 44, 53, 54). Threshold bronchoconstriction and depressor as well as bradycardic response were also augmented, although to a lesser extent. In all cases, the augmentation was abolished by blockade of NTS NK1 receptors.

In the present study, we relied on exogenous application of substance P to excite NTS neurons during synaptic transmission of bronchopulmonary C fiber input, presumably mediated primarily by glutamate. The results indicate that activation of substance P receptors can have a physiologically relevant effect by augmenting bronchopulmonary C fiber reflex output. They do not, however, address the question of the sources of endogenous release of substance P. Although substance P-containing soma and axons are located throughout the CNS (18), most studies have focused on substance P content in vagal afferent fibers. The findings that substance P is 1) synthesized in the nodose and jugular ganglia (24, 27), 2) present in the vagus nerve (24, 27), and 3) reduced in the NTS after nodose ganglionectomy (24, 27) are consistent with a neural network for the release of substance P from vagal sensory afferent fibers, including the bronchopulmonary C fibers. The same synthesis and release mechanisms in vagal sensory afferent fibers also exist for glutamate (33, 41, 47). In addition, electrophysiological evidence suggests that glutamate is the primary neurotransmitter of vagal sensory input to the NTS. First, results obtained in NTS slices indicate that glutamate released from visceral sensory afferent fibers activates the ionotropic glutamate receptors AMPA and NMDA (2), and activation of the AMPA receptors is sufficient for synaptic generation of action potentials in the second-order neurons (1). Secondly, data obtained from extracellular recordings in the whole animal also indicate that bronchopulmonary C fiber synaptic input to the NTS is mediated by glutamate acting largely at AMPA receptors (53, 54). Interestingly, in the whole animal studies, the C fiber input was attenuated to the same extent (by ~65%) whether both AMPA and NMDA receptors were blocked or whether just AMPA receptors were blocked, raising the possibility that other mediators may be required for full expression of synaptic transmission. Finally, although iontophoretic application of either glutamate or substance P produces excitatory responses of individual NTS neurons in most studies (19, 28, 29, 42, 55), the onset and recovery of the substance P-induced increased spiking activity are slower compared with glutamate-evoked responses (29), suggesting substance P may provide a more sustained excitatory input.

Taken together, the data are consistent with the idea that although glutamate may be required for mediating fast synaptic transmission of bronchopulmonary C fiber input to the NTS, the coincident release of substance P at these synapses (either from vagal afferent terminals or other sources) can increase the excitability of postsynaptic neurons, perhaps augmenting the responsiveness to glutamatergic transmission. There is precedent for postsynaptic interactions between glutamate and substance P in the NTS. Near-threshold increases in TE evoked by NTS injections of DL-homocysteine, which activated both NMDA and AMPA receptors, were augmented 10-fold by a background injection of substance P (5).

That substance P was acting via an NK1 receptor mechanism is suggested by the abolition of the substance P-induced augmentation of the reflex responses by blockade with the high-affinity NK1 receptor antagonist CP-96345. A recent report has indicated that CP-96345 can interact with L-type voltage-dependent calcium channels by mechanisms unrelated to tachykinin receptor antagonism (49). However, CP-96344, the inactive enantiomer that has similar actions at L-type calcium channels but no NK1 receptor antagonist properties, had no effect on the substance P-evoked responses. Thus it seems likely that the CP-96345 effects on the substance P responses were due to NK1 receptor antagonism. Interestingly, Mazzone and Geraghty (40) found that large injections of capsaicin (500 nl) in the NTS produced a delayed slowing of breathing frequency in spontaneously breathing rats. Unlike the response in the present study, which peaked <5 s (Fig. 4), in their study there was no detectable change in breathing frequency until 5-10 min after the NTS injections. Furthermore, in the present study, the response was abolished by NK1 receptor antagonism, whereas in their study the response was attenuated by blockade of the neurokinin-A (NK2) receptors with SR-48968 and neurokinin-B (NK3) receptors with SR-142801 but not by the substance P NK1 receptors with RP-67580. Given that the two responses were much different in terms of time course and response to antagonists, it is unlikely that the responses were related (39). It should also be noted that there appears to be some species variability in tachykinin-NK1 receptor affinity for certain NK1 receptor antagonists. Barr and Watson (3) found that two nonpeptide NK1 receptor antagonists, CP-96345 and RP-67580, had an ~200-fold greater affinity for human and guinea pig NK1 receptors than for rat NK1 receptors.

In an NK1 receptor-knockout mouse, the respiratory slowing evoked by right atrial phenyl biguanide injections appeared to be blunted (~40%), however, the trend did not reach statistical significance. The data raise the possibility that endogenous substance P via activation of NK1 receptors may not play a major role in bronchopulmonary C fiber signal transmission in the NTS in normal mice (10). The effect of exogenous substance P on the bronchopulmonary C fiber reflex was not determined in their study. However, if more substance P were released, either from activation of other inputs or under conditions of enhanced release from the bronchopulmonary C fibers such as may occur as a consequence of allergic inflammation (22), they may have observed a blunting of the enhanced response in the knockout mice.

Finally, substance P actions in the NTS appear to provide a general mechanism for modulating autonomic reflexes. A large body of data from studies using microinjections of substance P, NK1 receptor agonists, or NK1 receptor antagonists in the NTS suggest that substance P either transmits or augments baroreceptor or cardiac C fiber receptor-mediated decreases in blood pressure and HR (12, 17, 21, 25, 35, 45) as well as modulates peripheral carotid chemoreceptor signaling (24, 51).

In summary, exogenously applied substance P in the NTS augments bronchopulmonary C fiber reflex output. Because substance P synthesis in airway C fibers may be enhanced in certain pathological conditions, such as allergic asthma, the findings may help explain some symptoms including cough, bronchoconstriction, and mucus hypersecretion.

Perspectives

There is considerable evidence that substance P, synthesized in vagal cell bodies in the nodose and jugular ganglia, is transported peripherally to the vagal C fiber endings within the airways, where with stimulation it is released via local reflex pathways. The release of substance P can cause airway hyperresponsiveness, bronchoconstriction, and neurogenic edema, symptoms of allergic asthma (36, 48). The current findings that substance P can augment bronchopulmonary C fiber reflex output may provide a link between a tightly coordinated release of substance P locally and centrally to exaggerate the C fiber-evoked responses, which also include airway hyperresponsiveness, bronchoconstriction, edema, and perhaps cough. The possibility that endogenous release of substance P can exaggerate components of the bronchopulmonary defense reflex raises the question as to under what conditions the neuropeptide might be released from the afferent fibers. Indeed, certain pathophysiological conditions may be associated with increased substance P release. Fischer and colleagues (22) have shown that exposure to inhaled allergens increases the synthesis of substance P message and content in the nodose ganglia. This plasticity of the expression of substance P specifically in the sensory ganglia of the vagus nerve raises the possibility that under conditions of inhaled allergens, the increased substance P could be transported centrally and released in the NTS to augment the defensive bronchopulmonary C fiber reflex responses.


    ACKNOWLEDGEMENTS

The authors gratefully acknowledge the excellent technical support provided by Judy Stewart and Amy Radbill.


    FOOTNOTES

This research was supported by funds from the National Institute of Environmental Health Sciences Grant ES-00628 and the California Tobacco-Related Disease Research Program Grant 6RT-0024. T. Mutoh is supported by a Research Fellowship of the Japan Society for the Promotion of Science for Young Scientists.

Address for reprint requests and other correspondence: J. P. Joad, Univ. of California, Davis, Dept. of Pediatrics, Ticon II, 2516 Stockton Blvd., Sacramento, CA 95817 (E-mail: jpjoad{at}ucdavis.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 17 March 2000; accepted in final form 18 May 2000.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Am J Physiol Regul Integr Comp Physiol 279(4):R1215-R1223
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