Chem. Senses 28: 253-259,
2003
© Oxford University Press 2003
Lack of Quinine-evoked Activity in Rat Trigeminal Subnucleus Caudalis
Section of Neurobiology, Physiology and Behavior, University of California, Davis, 1 Shields Ave., Davis, CA 95616, USA 1 Laboratorie de Physiologie de la Manducation, Université Paris 7, Paris, France
Correspondence to be sent to: C.T. Simons, Section of Neurobiology, Physiology and Behavior, University of California, Davis, 1 Shields Ave., Davis, CA 95616, USA. e-mail: ctsimons{at}ucdavis.edu
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Abstract |
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Conflicting reports exist regarding the ability of quinine to activate neurons in the trigeminal system. We used the complementary approaches of single-unit electrophysiology and c-fos immunohistochemistry to investigate whether quinine (100 mM) activates chemonociceptive cells in the brainstem trigeminal subnucleus caudalis (Vc). In electrophysiological experiments, 38 units responded to noxious mechanical, thermal and chemical (200 mM pentanoic acid) stimuli applied to the tongue with an increase in firing rate; none responded to lingual quinine whether the quinine was presented before or after application of pentanoic acid. In the c-fos immunohistochemical experiment, both quinine and water elicited equivalent levels of fos-like immunoreactivity (FLI) in dorsomedial Vc that were significantly lower than the level of FLI evoked by pentanoic acid. These data collectively indicate that quinine does not elicit activity in chemonociceptive Vc neurons.
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Sensations of taste and oral irritation are thought to be processed separately via gustatory and somatosensory pathways, respectively. Indeed, prototypical taste stimuli applied to the tongue activate peripheral neurons that project to the brainstem taste relay, the nucleus of the solitary tract (NTS) (Herness and Gilbertson, 1999
; Smith and St John,
1999). In contrast, irritant stimuli excite small diameter
nociceptive neurons that project to the caudal aspect of the brainstem
trigeminal complex (Vc) (Sostman and
Simon, 1991; Carstens et
al., 1998). Interestingly, the tastants NaCl and citric acid,
when delivered to the tongue at high concentrations, elicit neuronal activity
in Vc (Carstens et al.,
1998; Sudo et al.,
2002), as well as sensations of irritation
(Green and Gelhard, 1989;
Gilmore and Green, 1993;
Dessirier et al.,
2000a,
2001).
Recently, several reports have indicated that quinine is able to activate
lingual trigeminal afferents (Lundy and
Contreras, 1994; Pittman and
Contreras, 1998) or increase intracellular calcium in trigeminal
ganglion neurons (Liu and Simon,
1998). Despite this evidence, there have been no reports of
quinine inducing sensations of irritation when applied to the human tongue in
psychophysical experiments. Indeed, in human studies directly addressing this
issue, no subject reported quinine as having any sensation other than bitter
(B.G. Green, personal communication). The physiological and psychophysical
results, therefore, appear dichotomous.
It is commonly accepted that taste provides important information regarding
nutritional and qualitative aspects of ingested items [for review, see Scott
and Verhagen (Scott and Verhagen,
2000)]. Chemesthesis, on the other hand, conveys information
regarding the presence of noxious and potentially dangerous chemicals
(Green et al., 1990;
Green and Lawless, 1991). Thus
it makes adaptive sense that poisonous alkaloids, which typically taste
bitter, might activate both taste and trigeminal pathways. In this way,
parallel pathways would ensure the detection of deleterious chemicals, in turn
initiating oromotor responses that result in their rejection. In the current
study we employed two complementary techniques, electrophysiology and c-fos
immunohistochemistry, to explore the possibility that quinine excites neurons
in Vc.
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Materials and methods |
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Animals
Thirty-eight male Sprague–Dawley rats (Simonsen, Gilroy, CA) weighing
450 g were used in these experiments. They were housed two per cage in a
vivarium maintained on a 12 h:12 h light:dark cycle (light on at 7 a.m.) at
21°C and allowed food and water ad libitum. All procedures
were in accordance with the NIH animal welfare guidelines and approved by the
UC Davis Animal Use and Care Committee.
Experiment 1: electrophysiology
Surgery
Rats (n = 20) were anesthetized with thiopental (55 mg/kg; i.p.)
and core body temperature was maintained at 37°C by placing the
animal under a heating lamp. The jugular vein was cannulated to allow constant
infusion of thiopental (10 mg/kg per h) and a tracheal cannula was placed to
assist breathing. A dorsal midline incision was made and the caudal brainstem
and upper cervical spinal cord exposed by removal of the atlanto-occipital
membrane and caudal portion of the occipital bone. Animals were fixed into a
stereotaxic frame (David Kopf Instruments, Tujunga, CA) with their head
ventroflexed (to expose obex) and the upper cervical spine immobilized with a
vertebral clamp. The dura mater was removed and agar (Difco, Detriot, MI)
poured over the brainstem. After hardening, an opening was cut through the
agar in an area overlying Vc and filled with 0.9% saline. Finally, a small
clip was placed over the incisors to hold open the mouth and allow access to
the anterior tongue. Physiological saline was applied to the lingual surface
to prevent desiccation.
Recording
A Teflon-insulated tungsten recording electrode (10 M
; F. Haer
Inc. Brunswick, ME) was advanced into the brainstem (1.5 mm lateral to
obex) using a hydraulic microdrive (David Kopf Instruments). Single unit
recordings were made from nociceptive neurons in superficial laminae (<300
µm) of the dorsomedial Vc having receptive fields on the ipsilateral
anterior tongue. Extracellular activity was amplified, digitized and fed to a
computer for later analysis at which time unitary action potentials were
discriminated and counted by custom software
(Forster and Handwerker,
1990).
Stimulation
Vc units responsive to heat (55°C) and pinch were isolated and further
tested for chemosensitivity using pentanoic acid (200 mM dissolved in
deionized water; Sigma Chemicals, St Louis, MO; pH 3.0). Only chemonociceptive
units were selected for further study. Pentanoic acid was applied via syringe
as a bolus (0.3 ml) to the dorsal surface of the tongue and rinsed 90 s later
with deionized water (2 ml). Quinine–HCl (100 mM dissolved in
deionized water, pH 5.8; Sigma Chemicals) was applied in an identical manner.
This concentration, which was equal to
(Kawamura et al.,
1968; Sostman and Simon,
1991) or higher (Lundy and
Contreras, 1994; Liu and
Simon, 1998; Pittman and
Contreras, 1998) than concentrations used in other experiments,
was selected to increase the chance of exciting units. All chemicals were
applied at room temperature.
Chemical stimuli were applied successively to the lingual surface at interstimulus intervals of 5 min. Pentanoic acid was applied twice, followed by quinine, followed again by pentanoic acid. Thus, the duration of each experiment lasted <30 min. In 11 animals, recordings were made from additional units, usually on the same side, isolated and tested in the same manner (average 2–3 units/rat). A minimum of 30 min elapsed between successive recordings in animals from which multiple units were isolated.
Using the current stimulation parameters, pentanoic acid neither sensitizes
nor desensitizes subsequent noxious-evoked responses of Vc neurons
(Dessirier et al.,
2000b; Sudo et al.,
2002) and we believe that it was unlikely to affect Vc
responsiveness to quinine. Nevertheless, to eliminate this possibility, we
reversed the order of stimulus presentation so that quinine preceded pentanoic
acid. This required us to test responses of Vc neurons to quinine prior to any
other chemical stimulation of the tongue. To increase the likelihood that the
Vc neuron was chemonociceptive, in each of seven rats, we selected a neuron
that responded to the noxious thermal stimulus because there is a good
correspondence between heat- and pentanoic acid-sensitivity
(Dessirier et al.,
2000b). Heat-responsive Vc neurons were then tested with quinine
delivered in the same manner as described above, followed 5 min later by
pentanoic acid to confirm that the Vc unit was chemonociceptive.
Histology
Following the completion of the last recording for each animal, an
electrolytic lesion was made at the recording site by passing current (6 V DC)
through the microelectrode for 45 s. Animals were killed with an overdose of
thiopental (100 mg/kg; i.v.) and the brains were removed and fixed in 10%
formalin. Not less than 1 week later, the brains were frozen, cut into 50
µM sections, collected onto glass slides and counterstained with neutral
red. Lesions were identified under a light microscope and collectively plotted
onto a representative brainstem section (Figures
2C and
3B).
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Data analysis
To determine if pentanoic acid or quinine elicited activity above baseline
levels, each unit's response was integrated into 1 or 60 s bins (baseline:
0–60 s, initial response: 61–120 s, late response: 121–180
s) and analyzed using analysis of variance (ANOVA; animal and time as main
effects). To determine if the magnitude of Vc responses elicited by pentanoic
acid was different from that elicited by quinine, unit responses to each of
the stimulus trials were integrated (60–150 s) and subjected to ANOVA
(animal and trial as main effects). A P < 0.05 was taken as
significant and all data are presented as means ± SE.
Experiment 2: immunohistochemistry
Stimulation
Animals (n = 18) were anesthetized with pentobarbital (65 mg/kg;
i.p.) and a clip was placed over the upper and lower incisors to keep the
mouth open and provide access to the tongue. Animals received either quinine
(100 mM; n = 6), pentanoic acid (200 mM; n = 6) or deionized
water (n = 6) delivered to the anterior third of the tongue by
syringe. For all groups, the stimulus was applied gently as a bolus (0.3
ml) at time 0 and again 15 min later. To minimize any confounding
mechanosensory-induced labeling, stimuli were not rinsed. The clip was gently
removed 20 min after the last stimulus and the animals were closely monitored
until they were killed by perfusion.
Staining
Two hours after the onset of lingual stimulation, each animal was perfused
through the heart with 250 ml of phosphate-buffered saline (PBS) followed
immediately by 500 ml of 4% paraformaldehyde. The brains were removed,
post-fixed in 4% paraformaldehyde for 24 h and transferred to a 30%
sucrose solution for cryoprotection. One to 2 days later, the brains were
frozen, cut into 50 µm sections and processed for c-fos
immunohistochemistry as previously described
(Simons et al.,
1999). Briefly, the sections were first blocked with 3% normal
goat serum (in PBS with 0.3% Triton X-100) and then exposed to the primary
c-fos antibody (diluted 1:50 000; Arnel Products Inc., New York, NY) for
24–36 h. The primary antibody was removed and the sections washed
followed by application of the secondary biotinylated goat anti-rabbit
antibody (Vector Laboratories, Burlingame, CA). One hour later, this antibody
was removed, the sections were washed again, subjected to the
avidin–biotin–peroxidase reaction and cell nuclei expressing
fos-like immunoreactivity (FLI) were stained black by a nickel
diaminobenzidine reaction. Brainstem sections were mounted and coverslipped on
glass slides for later microscopic analysis.
Data analysis
All sections were examined under the light microscope (Nikon E-400) and
cell nuclei displaying black FLI were counted bilaterally between the level of
the pyramidal decussation caudally up to the rostral pole of the nucleus of
the solitary tract (NTS) in five regions of interest: (i) dorsomedial Vc, (ii)
ventrolateral Vc, (iii) the caudal NTS up to the level of the area postema,
(iv) the gustatory NTS from the area postrema (AP) through the rostral pole
and (v) the ventrolateral medullary area dorsal to the lateral reticular
nucleus. The dorsomedial Vc region was restricted to the area within the gray
matter and 50 µm medial to it. The ventrolateral Vc region was restricted
to the gray matter and fiber bundles within 50 µm of the medial gray matter
border. These restrictions delimited the Vc regions from the more medially
situated NTS dorsally and the ventrolateral medullary area ventrally
(Carstens et al.,
1995). Counts of FLI were made in each of the five regions
bilaterally at 150 µm intervals. The investigator who did counts of FLI was
blinded as to the experimental treatment. For each treatment group, total FLI
in each region of interest was divided by the number of sections examined to
yield mean FLI/section. The numbers of FLI expressing neurons in each area of
interest were compared between treatment groups using ANOVA (treatment group
as main effect) followed by post hoc LSD tests; a P value of
<0.05 was considered to be significant. For illustrations, selected
sections were imaged with a color video camera (Dage MTI DC-330) using Scion
Image software and superimposed on line drawings of sections taken from the
atlas of Paxinos and Watson (Paxinos and
Watson, 1998) to plot distributions of FLI
(Figure 4).
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Results |
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Electrophysiology
Thirty-eight units responded to noxious heat (54°C) and pentanoic acid. Of these, 26 responded to non-noxious mechanical stimulation and were categorized as wide dynamic range (WDR) type whereas 12 responded only to noxious mechanical stimulation (pinch) and were categorized as nociceptive-specific. Spontaneous activity in these units was generally low and seldom exceeded 5 Hz. Mechanical receptive fields were limited to the ipsilateral tongue and occasionally included the ipsilateral lip. An example of such a recording is shown in Figure 1.
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The initial pentanoic acid stimulus elicited a mean response in these
neurons that was significantly [F(2,56) = 40.2; P <
0.001] higher than baseline activity and peaked 45 s following the
stimulus onset (Figure 2A).
Subsequent pentanoic acid trials elicited responses that were of equal
magnitude [LSD: P(1 versus 2) = 0.248, P(1 versus 3) =
0.102, and P(2 versus 3) = 0.609] and temporal structure (Figure
2B,D).
Lingual quinine application, however, did not evoke activity above basal
levels (Figure 2C) when
analyzed in 1 s [F(209,5852) = 1.113; P = 0.130] or 60 s
bins [F(2,56) = 0.1; P = 0.938]. Indeed, the magnitude of
the mean quinine response was not different from pre-stimulation baseline but
was significantly smaller than any response elicited by pentanoic acid
stimulation [F(3,84) = 42.4; P < 0.001].
In seven heat-responsive units, quinine was tested prior to pentanoic acid. In these units, lingual quinine application did not evoke activity above basal levels [F(2,12) = 0.888, P = 0.437; Figure 3A] whereas the pentanoic acid stimulus elicited activity in each of the seven units that was, on average, significantly [F(2,12) = 12.2, P < 0.001] higher than spontaneous levels (Figure 3B). In these seven units, pentanoic acid evoked significantly [F(1,12) = 26.8, P < 0.001] larger responses compared with quinine, confirming that quinine applied either before or after pentanoic acid does not excite chemonociceptive Vc units.
Immunohistochemistry
Figure 4 shows individual
examples of the distribution of FLI (dots) at three representative brainstem
levels following application of pentanoic acid (A), quinine (B) or water (C).
There were no significant differences in counts of FLI between the quinine and
water (vehicle control) treatment groups for any of the brainstem regions
analyzed (Figure 5). In the
dorsomedial aspect of Vc, corresponding to where our electrophysiological
recordings were made, pentanoic acid elicited significantly [F(2,15)
= 14.6; P < 0.001] higher mean counts of FLI compared with quinine
or water (Figure 5, Vc dm).
Using identical methods, we previously reported that there was no FLI in
dorsomedial Vc in control animals not receiving any stimulus to the tongue
(Simons et al.,
1999). Thus, the FLI that was seen following quinine and water
(9) might reflect a low level of activation of the Vc neurons by
mechanical and/or thermal components of the stimulus. There were no
significant differences among treatment groups for any of the other brainstem
regions, including the rostral aspect of NTS
(Figure 5; NTSr). In
particular, we did not observe increased FLI at the rostral pole of NTS
(Figure 4A-C, uppermost
sections) following application of any of the stimuli.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Complementary immunohistochemical and electrophysiological methods were used to test the hypothesis that the bitter tastant quinine would activate chemonociceptive neurons in the brainstem trigeminal complex. Presently, we found that a high concentration of quinine applied to the tongue was unable to excite individual chemonociceptive Vc units or evoke FLI in dorsomedial Vc.
Early studies indicated that a high concentration of quinine was incapable
of exciting lingual nerve fibers when applied to the tongue
(Kawamura et al.,
1968) even though these same fibers responded well to high salt
concentrations. Subsequent studies confirmed that lingual fibers were
responsive to high concentrations of salts and acids but failed to respond
consistently to quinine (Sostman and
Simon, 1991). However, these results are contradicted by more
recent evidence indicating that quinine elicits relatively small (±2
spikes from baseline) and transient (within the first 2 s) responses in
thermally sensitive trigeminal afferents
(Pittman and Contreras, 1998).
Similarly, quinine was shown to increase intracellular calcium in cultured
trigeminal ganglion neurons (Liu and
Simon, 1998). These studies support behavioral data indicating an
increase in rat quinine rejection-thresholds following trigeminal
deafferentation (Jacquin,
1983). However, in the behavioral study, the increase in
quinine-rejection thresholds was thought to reflect a failure on the part of
the rat to respond to subtle gustatory cues following massive orosensory
alterations as well as changes in taste bud morphology
(Jacquin, 1983) as opposed to
a loss of trigeminally mediated quinine sensitivity.
Prior calcium imaging work on trigeminal ganglion neurons showed that
73% of cells responding to capsaicin also responded to quinine
(Liu and Simon, 1998)
suggesting that these cell types are involved in chemonociception. In the
present study, we took specific measures to ensure that the cells we recorded
from were involved in the processing of chemonociceptive stimuli. The majority
(26/38) of cells were of the wide-dynamic range type, responding to both
noxious and non-noxious somatosensory stimuli with the rest being
nociceptive-specific. All cells, however, responded robustly to pentanoic
acid, a stimulus capable of activating the vanilloid receptor VR-1
(Tominaga et al.,
1998). Indeed, we have used this stimulus in the past to identify
Vc cells responsive to capsaicin (Dessirier
et al., 2000b) and found a 100% correspondence to
capsaicin sensitivity. Despite our attempts to target cells most likely to
respond to a quinine stimulus, we saw no evidence of such activation. Indeed,
we specifically attempted to identify transient, short-lasting responses, such
as those reported earlier (Pittman and
Contreras, 1998), but found no evidence for the occurrence of such
activity in Vc. These findings were consistent with the c-fos results in which
the number of FLI-expressing neurons evoked by quinine was not different from
the number evoked following a water stimulus. Thus, whereas in some studies
quinine evoked small and transient responses in thermally sensitive lingual
fibers (Pittman and Contreras,
1998) or an increase in calcium in trigeminal ganglion cells
(Liu and Simon, 1998), these
effects do not appear to be translated as increased activity in Vc. There are
several explanations that may account for this discrepancy. First,
methodological and/or analytical variations may have contributed to the
observed differences. Whereas we selected cells based upon chemonociceptive
sensitivity, Pittman and Contreras
(Pittman and Contreras, 1998)
targeted thermally sensitive lingual fibers that responded to cooling.
Moreover, their analysis was biased to specifically identify very subtle
effects. Indeed, the criterion for a quinine-evoked response was a change in
impulse frequency that need only exceed ±1.96 standard deviations of
baseline activity. Secondly, although near the saturation limit for an aqueous
solution, the concentration of quinine used presently may have been
sub-threshold to activate chemonociceptive Vc neurons. We have noted on
numerous occasions that the concentrations used to activate chemonociceptive
Vc neurons far exceeds that needed to activate primary afferents from the
cornea or induce changes in membrane permeability of cultured trigeminal
ganglion cells (Carstens et al.,
1998; Dessirier et
al., 2000b; Simons et
al., 2003). Third, the relatively small effects of quinine on
lingual nerve fibers may be insufficient to excite Vc neurons that presumably
receive considerable convergence from multiple trigeminal primary afferents.
Lastly, the increased Ca2+ signal evoked by quinine in isolated
trigeminal ganglion neurons (Liu and
Simon, 1998) may reflect methodological anomalies such as thermal
changes associated with stimulus delivery. Indeed, this increased calcium may
not necessarily even have been sufficient to evoke action potentials in the
afferent fiber. Alternatively, because quinine has been shown to alter
membrane conductance in neuroblastoma x glioma hybrid cells
(Robbins et al.,
1992), the intracellular calcium increase reported in trigeminal
ganglion cells may be the result of non-specific effects on membrane
permeability.
Finally, it is of interest to note that presently, we found no evidence
that quinine evoked greater FLI at the rostral pole of NTS than did water or
pentanoic acid. In prior studies using awake, behaving animals, quinine was
shown to evoke FLI along the medial aspect of the gustatory NTS suggesting the
possibility of a rudimentary chemotopic map at this level of the central
nervous system (Harrer and Travers,
1996; King et al.,
1999; Travers et al.,
1999; Travers,
2002). There are several explanations that might underlie this
difference. The anesthetic (pentobarbital) used in the present experiments may
well have blunted the neuronal taste responses to quinine, thus reducing the
occurrence of FLI in the gustatory NTS. Moreover, in the present study,
quinine was applied only to the anterior tongue thus exciting neurons
predominantly of chorda tympani origin whereas in the awake behaving
preparation, quinine is given through intraoral cannulae and thus activates
gustatory neurons of chorda tympani as well as glossopharyngeal and vagal
origin. Recent evidence suggests that the quinine-evoked FLI in the gustatory
NTS is elicited primarily through glossopharyngeal afferents that terminate
largely in the dorsomedial portion of this nucleus (King et al.,
1999,
2000).
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Acknowledgments |
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This work was supported by grants from the California Tobacco-Related Disease Research Program, no. 10DT-0197, 11FT-0101 and 11RT-0053, the National Institute of Dental and Craniofacial Research, no. DR13685, and the International Association for the Study of Pain.
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Accepted March 4, 2003
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