1Faculty of Dentistry, The University of Toronto, Toronto, Ontario M5G 1G6, Canada; 2Center for Sensory-Motor Interaction, Laboratory for Experimental Pain Research, Aalborg University, DK-9220 Aalborg; and 3Department of Prosthetic Dentistry and Stomatognathic Physiology, Orofacial Pain Clinic, Royal Dental College, Aarhus University, DK-8000 Aarhus, Denmark
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Cairns, Brian E., James W. Hu, Lars Arendt-Nielsen, Barry J. Sessle, and Peter Svensson. Sex-Related Differences in Human Pain and Rat Afferent Discharge Evoked by Injection of Glutamate Into the Masseter Muscle. J. Neurophysiol. 86: 782-791, 2001. Animal studies have suggested that tissue injury-related increased levels of glutamate may be involved in peripheral nociceptive mechanisms in deep craniofacial tissues. Indeed, injection of glutamate (0.1-1 M, 10 µl) into the temporomandibular region evokes reflex jaw muscle responses through activation of peripheral excitatory amino acid receptors. It has recently been found that this glutamate-evoked reflex muscle activity is significantly greater in female than male rats. However, it is not known whether peripheral administration of glutamate, in the same concentrations that evoke jaw muscle activity in rats, causes pain in humans or activates deep craniofacial nociceptive afferents. Therefore we examined whether injection of glutamate into the masseter muscle induces pain in male and female volunteers and, since masseter afferent recordings were not feasible in humans, whether glutamate excites putative nociceptive afferents supplying the masseter muscle of male and female rats. Injection of glutamate (0.5 M or 1.0 M, 0.2 ml) into the masseter muscle of both men and women caused significantly higher levels of peak pain, duration of pain, and overall pain than injection of isotonic saline (0.2 ml). In addition, glutamate-evoked peak and overall muscle pain in women was significantly greater than in men. In rats of both sexes, glutamate (10 µl, 0.5 M) evoked activity in a subpopulation of masseter muscle afferents (n = 36) that projected to the subnucleus caudalis, an important relay of noxious input from the craniofacial region. The largest responses to glutamate were recorded in muscle afferents with the slowest conduction velocities (2.5-5 m/s). Further, glutamate-evoked masseter muscle afferent activity was significantly greater in female than in male rats. These results indicate that glutamate injection into the masseter muscle evokes pain responses that are greater in women than men and that one possible mechanism for this difference may be a greater sensitivity to glutamate of masseter muscle afferents in females. These sex-related differences in acute experimental masseter muscle pain are particularly interesting given the higher prevalence of many chronic muscle pain conditions in women.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Chronic pain from deep craniofacial tissues is a
common affliction, and perhaps as many as 10% of the North American
population will suffer, for example, from a temporomandibular disorder
(TMD) at some point in their lifetime (Carlsson and LeResche
1995; Drangsholt and LeResche 1999
). TMD pain is
frequently reflected in masticatory muscle pain, limited jaw motion,
and headache, is often poorly localized, and may spread and be referred
to the neck, face, or preauricular regions (see Carlsson and
LeResche 1995
; Sessle 2000
; Stohler
1995
, 1999
). There is a much greater prevalence
of TMD and related craniofacial pain conditions among women of
reproductive age, which suggests that sex-related factors may play a
role in the pathogenesis of these conditions. Nonetheless, the
mechanisms underlying these sex-related differences in the prevalence
of craniofacial pain remain obscure and could involve a variety of factors, including physiological and psychosocial factors
(Carlson et al. 1998
; Carlsson and LeResche
1995
; Dao and LeResche 2000
; Dao et al.
1998
; LeResche et al. 1997
; Maixner et
al. 1995
; Salonen et al. 1990
).
To investigate physiological factors that may underlie the development
of pain in deep craniofacial tissues, we have examined the effect of
injecting algesic substances into the temporomandibular joint (TMJ)
region on the activity of rat jaw muscles. Our most recent evidence
indicates that injection of the excitatory amino acid (EAA) glutamate
into the TMJ region reflexly evokes activity in the jaw muscles that is
greater in female rats than male rats (Cairns et al.
1998, 2001
). This result raises the possibility that there may be distinct sex-related differences in some of the
mechanisms involved in the processing of sensory inputs from deep
craniofacial tissues and that these differences may contribute to the
greater prevalence of many chronic muscle pain conditions in women.
This result also raises several important questions about peripherally
applied glutamate, including whether injection of glutamate in the same
concentrations applied to animals would evoke pain in humans and, if
so, whether there would be differences between men and women in their
reports of pain.
A well-documented experimental model of human masticatory muscle pain
has used the injection of hypertonic saline and other algesic chemicals
into the masseter muscle to evoke pain responses in healthy subjects
(Ernberg et al. 2000; Stohler and Kowalski 1999
; Svensson et al. 1995
, 1996
,
1999
; Zhang et al. 1993
). The present
study employed an analogous experimental craniofacial pain model to
test the hypotheses that injection of glutamate into the human masseter
muscle evokes pain when applied in the same concentrations that evoked
jaw muscle responses in the rat and that the intensity of this pain is
greater in women than men. In addition, since recording the activity of
single masseter muscle afferents was not feasible in humans, muscle
afferent recordings were undertaken in rats to characterize the effect
of glutamate on slowly conducting, putative nociceptive afferents and
to test the hypothesis that glutamate evokes greater activity recorded in muscle afferents of female rats than male rats.
![]() |
METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Human experiments
SUBJECTS.
Healthy volunteers without signs or symptoms of TMD (Dworkin and
LeResche 1992) were recruited from university students. The relationship between pain and different concentrations of glutamate following a single injection of glutamate into the masseter muscle was
initially determined in 10 women and 8 men. In the next human experiment, repeated injections of glutamate were given into the masseter muscle in 17 women and 16 men. Five men participated in both
experiments, which were separated by at least 2 mo. The age of the
women (26.0 ± 3.1 yr old, mean ± SE) and men (25.2 ± 2.9 yr old) was not significantly different (P = 0.444, unpaired t-test). The weight of the women and men was
60.8 ± 1.5 kg and 83.2 ± 3.3 kg, respectively
(P = 0.001, unpaired t-test). Twelve of the
27 women tested used oral contraceptive medication containing estrogen.
The self-reported onset date of the last menses was recorded, and none
of the women participating in the study reported irregular menstrual
cycles. The study protocol was approved by the local ethics committee
in Denmark (Counties of Nordjylland and Viborg) and followed the
guidelines set out by the Helsinki Declaration.
GLUTAMATE ADMINISTRATION.
Single injection.
Sterile solutions of glutamate (0.2 ml; 0.1, 0.5, 1.0 M; pH 6.8) or
isotonic saline (0.2 ml; 0.165 M; pH 7.0) were injected over a 10-s
period with a 27-gauge hypodermic needle and disposable syringe into
the deep masseter muscle midway between its upper and lower border and
1 cm posterior to its anterior border (Svensson et al.
1995). The needle was inserted to a depth until bony contact was made, and then it was retracted about 2 mm before aspiration and
injection of the solution. In all experiments, subjects were given
standardized instructions and were unaware of which solution was about
to be injected (single blind). To avoid sequence effects, injections of
glutamate (0.1, 0.5, and 1.0 M) and isotonic saline into the masseter
muscles were performed in a randomized fashion during two sessions
separated by 1 wk. Numbers were drawn to determine the sequence of
substance injection. At each session, the first injection was made into
either the left or right masseter muscle, and then 30 min later, a
second injection was made into the masseter muscle on the opposite
side. The site of the first injection was chosen at random. During the
second session, the two remaining substances were injected in
association with the same protocol.
|
Rat experiments
ANIMAL PREPARATION.
Adult male (n = 16, weight: 362.5 ± 14.0 g)
and female (n = 20, weight: 280.5 ± 5.6 g)
Sprague-Dawley rats were prepared for acute in vivo recording of
trigeminal primary afferent activity under surgical anesthesia
(O2: 0.3-0.4 l/min; N2O:
0.6-0.7 l/min; halothane: 1.5-2%) (Cairns et al.
1998, 1999
, 2001
). A tracheal cannula was inserted and artificial ventilation initiated. The rat's
head was then placed in a stereotaxic frame, the skin over the dorsal
surface of the skull was reflected, and a trephination was made on the
left side of the skull to allow a microelectrode to be lowered through
the brain and into the trigeminal ganglion. A second incision was made
and the skin and muscle overlying the brain stem and upper cervical
spinal cord were removed, a C1 laminectomy was performed, and the dura
overlying the brain stem/cervical spinal cord was removed to facilitate
placement of a stimulating electrode in contact with the ipsilateral
caudal brain stem (subnucleus caudalis, Vc) or dorsal horn of the upper
cervical spinal cord). In female rats, a vaginal lavage was performed,
and epidermal cell examination revealed that five were in estrus, nine
in metestrus, and six in diestrus (Frye et al. 1992
;
Martinez-Gomez et al. 1994
).
STIMULATION AND RECORDING TECHNIQUES.
Single trigeminal primary afferent unit activity within the trigeminal
ganglion was recorded by a parylene-coated tungsten microelectrode (2 M, A-M Systems, Carlsborg, WA). The microelectrode was
slowly lowered into the brain under stereotaxic control (3.5-4 mm
anterior to the interaural line, 3-4 mm lateral to the midline) until
unit discharge was observed in response to light brush stimuli applied
to the craniofacial region. Trigeminal primary afferent units were
usually found 7-8 mm below the surface of the cerebral cortex. A blunt
probe was applied as a mechanical search stimulus over the masseter
muscle while the electrode was slowly lowered in an attempt to identify
trigeminal primary afferents with muscle mechanoreceptive fields. When
a unit was found that appeared to respond to mechanical stimulation of
the masseter muscle, the skin overlying the mechanoreceptive field was
pulled gently away from contact with the muscle, and brush, pinch, and
pressure stimuli were applied directly to the skin surface. If the unit
did not respond to any of these cutaneous stimuli, then the
mechanoreceptive field was considered to lie within the muscle.
It was observed that subsequent insertion of the catheter needle used
to inject glutamate into the masseter muscle evoked a spike discharge
in all muscle afferents identified in this manner (Paintal
1960
). At the completion of some experiments, the skin
overlying the masseter muscle was surgically excised, and it was
confirmed that mechanical and electrical stimuli applied directly to
the muscle tissue could also evoke activity in the afferent that
previously had been characterized by mechanical and glutamate
stimulation in the experiment.
TERMINAL PROCEDURES. At the end of each experiment, rats were killed with the agent T61 (Hoechst, Canada). Electrical lesions were made in the brain stem of some rats by applying a monopolar, monophasic current pulse of 20 µA for 20 s. The brain stem was then removed, and thin sections of the brain stem and upper cervical spinal cord (100 µm) were cut with a vibratome and viewed under a microscope.
DATA ANALYSIS. The activity of identified primary afferents was amplified (Afferent gain: ×1,000; bandwidth 30-1,000 Hz) and fed into a computer equipped with a CED 1401 Plus board and analysis software (Spike 2; Cambridge Electronic Design, Cambridge, UK). Recorded primary afferent activity was stored electronically and analyzed off-line.
Peristimulus time histograms (PSTHs; 1-min bins) were constructed from the recorded primary afferent discharge. Mean baseline afferent discharge was calculated by averaging the 1st 10 bins prior to injection of glutamate. Mean baseline afferent activity was subtracted from each bin of the PSTH to yield residual afferent discharge. The area under the glutamate-evoked afferent response curve (AUC) was calculated by the summation of the residual afferent discharge after glutamate injection (Cairns et al. 1998Statistics
Values are reported as means ± SE in the text and figures. In the human experiments the VAS scores were analyzed with a two-way ANOVA (gender and repeated injections or different glutamate concentrations as factors). The ANOVA was followed by post hoc comparisons with the use of Tukey tests. Weight and age was compared between women and men with the use of unpaired t-tests.
In the rat experiments, an unpaired t-test was used to compare the mean weight and conduction velocity of the male and female rats. A Mann-Whitney rank sum test was used to compare the peak and AUC values for male and female rats, and a Kruskal-Wallis one-way ANOVA on ranks was used to compare the AUC values for female rats in different estrus stages, since AUC and peak data were not normally distributed. A Wilcoxon signed-rank test was used to compare the masseter muscle afferent responses when repeated injections were made.
A Pearson product moment correlation was performed to assess the relationship between weight and VAS scores or afferent responses within male and female subject groups. In all tests, the level of significance was set at P < 0.05.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Human experiments
GENERAL FEATURES. All subjects described a deep, aching type of pain after the injections of 1 M glutamate. The majority of both the men and women did not localize the pain solely to the injected masseter muscle but also reported that it spread to involve other craniofacial tissues such as the TMJ and teeth ipsilateral to the site of injection (Fig. 1). There was a significant difference in the perceived area of pain (F = 4.935, P = 0.033, 2-way ANOVA) with significantly greater areas being measured on the drawings of the women (P = 0.034, Tukey test). There was, however, no significant difference area of pain produced by the first and second injections of glutamate (F = 0.205, P = 0.654, 2-way ANOVA) and no significant interaction between gender and repeated injection.
There were no significant differences in glutamate-evoked pain between the women taking oral contraceptive medication (n = 12) and those who did not (n = 15, P = 0.789, unpaired t-test). The women were not tested in any specific phase of the menstrual cycle, and the overall test dates were evenly distributed throughout the menstrual cycle. Although the mean weight in the men was significantly greater than that in the women (P = 0.001, unpaired t-test), there was no significant correlation between weight and glutamate-evoked pain in the men (rmen =SINGLE INJECTION. Different concentrations of glutamate were tested in 8 men and 10 women. The peak pain ratings and the VASAUC showed a significant difference between the men and women (F = 14.812, P = 0.001, 2-way ANOVA) with significantly higher pain responses for the women than for men (P = 0.001, Tukey test; Fig. 2, A and B). There was no significant gender difference for the time to peak pain (F = 0.004, P = 0.948, 2-way ANOVA). Furthermore, there were no significant interactions between sex and concentration, although the peak pain ratings and VASAUC in the women, but not the men, were slightly higher following injections of 1.0 M glutamate compared with 0.5 M glutamate.
|
REPEATED INJECTION. The pain responses evoked by two injections of 1.0 M glutamate into the masseter muscle were investigated in 16 men and 17 women. For all glutamate-evoked pain responses, there were significant differences between the women and men (Fig. 3, A-C). The peak VAS was significantly higher (F = 10.508, P = 0.003, 2-way ANOVA), the VASAUC significantly higher (F = 14.6, P = 0.001, 2-way ANOVA), and duration of response significantly longer (F = 9.486, P = 0.004, 2-way ANOVA) in the women than men. There was no significant sex-related difference in the time-to-peak VAS (F = 0.409, P = 0.527, 2-way ANOVA). There was no significant interaction between sex and repeated injections for any of the VAS parameters.
|
Rat experiments
GENERAL FEATURES. A total of 42 trigeminal primary afferents that responded to the blunt probe applied over the masseter muscle were recorded from the trigeminal ganglion of adult rats of either sex (Fig. 4). None of these afferents responded to brush, pinch, and pressure stimuli applied directly to the skin surface overlying the masseter muscle. All 42 masseter muscle afferents had antidromically identified projections to the caudal brain stem. Based on the distance from the obex where the electrical stimuli were applied, in concert with histological reconstruction of selected stimulation sites, all masseter muscle afferents could be antidromically activated from either the Vc or dorsal horn of the upper cervical spinal cord (Fig. 5A).
|
|
SINGLE INJECTION. A total of 16 and 20 glutamate-sensitive muscle afferents were recorded from male and female rats, respectively. Glutamate injection into the masseter muscle induced afferent activity with a latency of 3-10 s and a duration of 10-1,800 s. The glutamate-evoked afferent discharge exhibited a burst-pause firing pattern in 65 and 50% of masseter muscle afferents recorded in female and male rats, respectively. The proportion of afferents recorded in male and female rats with an action potential discharge greater than two SDs above their preinjection baseline activity (~95% confidence interval) for each minute postglutamate injection is illustrated in Fig. 6. In rats of both sexes, the activity of 10% of afferents remained elevated, relative to the preinjection baseline, for the duration of recording (30 min).
|
|
REPEATED INJECTION. In a subgroup of six masseter afferents (5 female, 1 male; CV: 12.1 ± 2.3 m/s), a second injection of glutamate was made 30 min after the initial injection of glutamate to compare the activity evoked by repeated injections (Fig. 8A). The magnitude of activity evoked by the second injection of glutamate (mean AUC2: 626 ± 379 spikes × min) was not significantly different from that evoked by the initial injection of glutamate to the masseter muscle (mean AUC1: 826 ± 474 spikes × min; P = 0.219, Wilcoxon signed-rank test). To investigate whether injection of a different amino acid would be equally effective in evoking masseter muscle afferent activity, for six masseter afferents (3 female, 3 male; CV: 11.3 ± 2.4 m/s), GABA (0.5 M; 750 mOsm/l) was injected into the masseter muscle 30 min after the initial injection of glutamate (Fig. 8B). The use of GABA also served to assess the possible effect of osmolarity since GABA and glutamate solutions were of comparable osmotic strength. Injection of GABA (mean AUC2: 5 ± 2 spikes × min) evoked significantly less activity than the initial injection of glutamate (mean AUC1: 220 ± 180 spikes × min; P = 0.031, Wilcoxon signed-rank test) in this subgroup of afferents.
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Glutamate-evoked responses in humans and rats
The present study shows that injection of glutamate into the masseter muscle can evoke pain in humans and also demonstrates that there are sex-related differences in both a human and animal model of deep craniofacial pain. We interpret these findings to be due, at least in part, to a local effect of glutamate, since in the human experiments, pain was reported in the craniofacial region on the same side as the injection, and in the animal experiments glutamate injections activated masseter muscle afferents.
Possible mechanisms
Several mechanisms may have been responsible for the
glutamate-evoked masseter muscle pain. To avoid the confound of low pH, glutamate solutions were adjusted to pH 6.8-7.4 prior to their injection, thus it is unlikely that the pain experienced was related to
the pH of the solution (Steen et al. 1992). The role of
mechanical distention in pain responses to glutamate was assessed by
the injection of the same volume of isotonic saline that resulted in
very low pain scores. Unlike pH, it was not possible to adjust the
osmolarity of the glutamate solutions, and it has been shown that
application of hypertonic saline to the human masseter muscle results
in pain reports that are qualitatively similar to those recorded in the
present study after intramuscular injection of high
concentrations of glutamate (Stohler and Kowalski 1999
;
Svensson et al. 1995
, 1996
,
1998
; Zhang et al. 1993
). Thus it is
possible that the osmotic strength of the glutamate solutions played a role in the reported pain responses. However, the injection of GABA of
comparable osmolarity and concentration to glutamate evoked significantly less afferent activity than glutamate, suggesting that
elevated osmotic strength is not likely to be a major factor responsible for the excitant effect of peripherally applied glutamate.
Activation of peripheral EAA receptors appears to play a role in
mechanisms of craniofacial pain transduction in rats and might also
have contributed to the pain reported in the present study by human
volunteers when the EAA glutamate was injected into the masseter muscle
(Cairns et al. 1998; Yu et al. 1996
). A
subpopulation of slowly conducting (A
and C) muscle afferents in
both humans and animals can be activated by locally applied intense
pressure and algesic chemicals and are thought to be associated with
muscle nociception (Fock and Mense 1976
; Kaufman
et al. 1982
; Kumazawa and Mizumura 1977
;
Marchettini et al. 1996
; Mense 1977
, 1993
; Paintal 1960
; Simone et al.
1994
). We found that injection of glutamate into the rat
masseter muscle evoked activity in A
mechanoreceptive afferents that
were shown to project to the caudal brain stem, a region documented to
be a critical relay of nociceptive input from jaw muscles as well as
other craniofacial tissues (Capra and Wax 1989
;
Nishimori et al. 1986
; Shigenaga et al.
1988
; see reviews by Hu et al. 1997
;
Sessle 2000
). Glutamate has been shown to excite
trigeminal afferents through activation of
N-methyl-D-aspartate (NMDA) and non-NMDA
receptors (MacIver and Tanelian 1993
; Pelkey and
Marshall 1998
; Puil and Spiegelman 1988
).
Further, reflex muscle responses can be evoked by activation of either
NMDA or non-NMDA receptors in deep craniofacial tissues (Cairns
et al. 1998
). This evidence suggests that activation of
peripheral EAA receptors may excite slowly conducting masseter muscle
nociceptors that contribute to pain responses in humans and is
consistent with the association between the development of hyperalgesia
and elevated tissue levels of glutamate elsewhere in the body
(Carlton et al. 1995
; Jackson et al.
1995
; Lawand et al. 1997
, 2000
;
McNearney et al. 2000
).
In our halothane-anesthetized rats, all masseter muscle afferents that
responded to both mechanical stimulation of the muscle and glutamate
injection had conduction velocities in the A range. The inability to
identify C afferents appears unrelated to the anesthetic employed,
since halothane has been reported to increase the excitability of
trigeminal C afferents but decrease the excitability of trigeminal A
afferents (MacIver and Tanelian 1990
). It may be
that masseter muscle C afferents were not activated by the mechanical
search stimuli employed. Nevertheless, it remains to be determined
whether C afferents innervating the masseter muscle would be similarly
activated by glutamate.
Effect of repeated injection
The present findings indicate that the area under the VAS pain
curve in humans and afferent activity in rats evoked by two injections
of glutamate into the masseter muscle is similar. These results suggest
that tachyphylaxis to the effect of repeated glutamate injection into
the masseter muscle at an interval of 25-30 min does not occur and are
consistent with previous reports that repeated injection of glutamate
into the TMJ region reflexly evokes jaw muscle activity of similar
magnitude (Cairns et al. 1998, 1999
). The
reproducibility of the responses in humans and rats to repeated injection of glutamate into the masseter muscle also may allow for
experimental designs to test the effects of analgesics on this type of
experimentally induced masseter muscle pain or afferent activity.
Sex-related differences in glutamate-evoked responses
Women rated injection of glutamate (0.5 and 1.0 M) into the
masseter muscle significantly more painful than men. Body weight and
the cross-sectional area of the masseter muscle is greater in men than
women, and it is conceivable that the greater VAS scores reported by
women could have been due to their smaller size (Close et al.
1995). However, we found no correlation between weight and pain
response in the men, and the correlation analysis in women showed that
larger weights were actually associated with higher pain scores. The
clinical significance of the latter finding is not known at present.
Furthermore, afferent discharges in male and female rats were not
correlated with body size, which suggests that muscle size as such
unlikely played a significant role in the observed differences in pain
ratings or muscle afferent activity.
Neither men nor women appeared to be able to discriminate between
masseter muscle injection of 0.5 M and 1.0 M glutamate. However, the
higher VAS scores in women than men were mirrored by a greater
glutamate-evoked muscle afferent discharge in female rats than male
rats. It appears therefore that sex-related differences in response to
glutamate may be at least partly explained by the greater responses of
masseter muscle primary afferents in females to glutamate.
Nevertheless, noxious stimulation of the deep tissues can also induce
prolonged changes in the excitability of both spinal cord and
trigeminal brain stem nociceptive neurons that may be greater in female
rats (see Bereiter et al. 1998; Hoheisel and
Mense 1989
; Hu et al. 1992
; Sessle
1999
, 2000
). The larger areas of perceived pain
reported by women after injection of glutamate into the masseter muscle
also suggest that central integrative mechanisms may contribute to the
observed sex-related differences. The size of perceived pain areas is
proportional to pain intensity (Graven-Nielsen et al.
1997
), and thus the greater pain intensity reported by women
may have been responsible for their reports of larger areas of
perceived pain. However, sex-related differences in focused attention
were not investigated in the present study, and this factor could also
have played a role in determining the size of perceived pain areas.
Previous studies have found that women report greater pain after
noxious thermal, electrical, or mechanical cutaneous stimuli than do
men, although because the reported magnitude of these differences has
often been small, the significance of this difference has been
questioned (Berkley 1995; Dao and LeResche
2000
; Fillingim and Ness 2000a
; Riley et
al. 1998
). Nevertheless, while men and women have a similar
ability to discriminate the intensity of noxious cutaneous thermal
stimuli, women report lower pain thresholds and greater pain during
repetitive thermal stimuli (Edwards et al. 1999
;
Fillingim et al. 1998
). The greater temporal summation of noxious cutaneous thermal stimuli in women has been interpreted as
evidence of a sex-related difference in central integration (Fillingim et al. 1998
; Maixner et al.
1995
).
Fluctuations in pain sensitivity during the menstrual cycle are
difficult to detect, particularly with small numbers of subjects (Fillingim and Ness 2000a,b
). In the present study, we
tested a relatively small number of subjects, and test dates were
evenly distributed throughout the menstrual cycle of women who were not taking oral contraceptives. The pain responses of these women were not
significantly different from the pain responses of women who reported
taking estrogen-containing contraceptives. In addition, no estrous
cycle stage-related differences in glutamate-evoked afferent activity
were noted in female rats. Thus we are not in a position to draw any
conclusions about the influence of menstrual cycle stage on magnitude
of glutamate-evoked masseter muscle pain in women. Nevertheless, we do
not exclude the possibility that menstrual cycle stage could exert some
influence on the magnitude of glutamate-evoked masseter muscle pain; an
effect that might be revealed by examining a larger population of women
(Dao et al. 1998
; LeResche et al. 1997
).
Clinical relevance
The prevalence of chronic pain conditions that include symptoms of
masseter muscle pain, such as TMDs and fibromyalgia syndrome, is
significantly greater in women than men (Bennett 1995;
Carlson et al. 1998
; Carlsson and LeResche
1995
; Dao and LeResche 2000
; LeResche et
al. 1997
; Maixner et al. 1995
). Interestingly,
while mechanical pain pressure thresholds for the masseter muscle are lower in fibromyalgia and TMD sufferers than in age- and sex-matched controls, sex-related differences in mechanical pain pressure threshold
have not been consistently found, and several methodological differences may account for this (see Bush et al. 1993
;
Dao and LeResche 2000
; Isselee et al.
1998
; Plesh et al. 1998
). In this regard, our
finding that injection of glutamate into the masseter muscle evokes
greater pain responses in women than men suggests that noxious chemical
as opposed to mechanical stimuli may be more useful for examining
sex-related differences related to the development of myalgia. In
addition, the injection of noxious chemicals in humans allows the
recording of both a temporal and a spatial pain profile (Figs. 1 and
2).
As noted above, peripheral glutamate receptors have been implicated in
the activation of primary afferents and in the development of
hyperalgesia after tissue injury (Cairns et al. 1998;
Carlton et al. 1995
; Du et al. 2001
;
Jackson et al. 1995
; Lawand et al. 1997
,
2000
; MacIver and Tanelian 1993
;
McNearney et al. 2000
; Pelkey and Marshall
1998
; Puil and Spigelman 1988
; Yu
et al. 1996
). In concert with the present study, such findings
point to a potential role for peripheral EAA receptors in the
modulation of pain arising from deep craniofacial tissues such as the
masseter muscle and TMJ. Further, our finding of a sex-related
difference in pain responses to peripherally injected glutamate
suggests that if selective peripheral EAA receptor antagonists can be
developed, they could be used to determine whether peripheral EAA
receptor activation is involved in the development or maintenance of
masseter muscle pain related to TMD or fibromyalgia syndrome in women.
![]() |
ACKNOWLEDGMENTS |
---|
The authors thank K. MacLeod, B. Cai, and Dr. K. Wang for technical assistance in the collection of data for this study.
This research was supported by National Institute of Dental and Craniofacial Research Grants DE-11995 and DE-04786 as well as a grant from the Danish National Research Foundation.
Present address of B. E. Cairns: Dept. of Anesthesia, Harvard Medical School/Children's Hospital, Boston, MA 02115.
![]() |
FOOTNOTES |
---|
Address for reprint requests: P. Svensson, Center for Sensory-Motor Interaction, Orofacial Pain Laboratory, Aalborg University, Fredrik Bajersvej 7 D-3, DK-9220 Aalborg SE, Denmark (E-mail: psv{at}smi.auc.dk).
Received 6 November 2000; accepted in final form 25 April 2001.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|