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Background and aims Preclinical studies have reported that activation of peripheral γ-aminobutyric acid A (GABAA) receptors may result in analgesia. The current study was conducted in young healthy men (n = 30) and women (n = 28) to determine whether injections of GABA into the masseter muscle reduce pain in a sex-related manner. Methods The effect of injection of GABA alone, or in combination with the non-inflammatory algogen glutamate, was assessed in two separate studies. Lorazepam, a positive allosteric modulator of the GABAA-receptor, was co-injected with GABA in both studies to explore the role of this receptor in muscle pain responses of healthy human volunteers. Masticatory muscle mechanical pain intensity was recorded on an electronic visual analogue scale (VAS) while muscle pain sensitivity was assessed by determining the pressure pain threshold (PPT), tolerance and maximal jaw opening (MJO) of the subjects prior to, and again after the various intramuscular injections. Results Intramuscular injection of GABA alone was reported to be significantly more painful, in a concentration related manner, than saline control injections, and this pain was further increased by co-injection of lorazepam with GABA. Co-injection of GABA with glutamate was found to significantly increase glutamate-evoked masseter muscle pain in men, but not in women. There was no effect of injections of either GABA alone, or GABA with glutamate, on PPT, tolerance or maximum jaw opening. Conclusions Injection of GABA into the human masseter muscle appears to excite nociceptors to produce muscle pain without a longer term effect on mechanical pain sensitivity in the muscle. The findings suggest that GABA-mediated pain in humans is produced through peripheral GABAA receptor activation. The mechanism underlying the sex-related difference in the effect of GABA on glutamate-evoked muscle pain was speculated to be due to a methodological artifact. Implications This study was designed to detect analgesic rather than algesic effects of peripherally administered GABA, and as a result, the concentration of glutamate chosen for injection was close to the maximal pain response for healthy women, based on previously determined pain-concentration response relationships for glutamate. This may explain the finding of greater pain in men than women, when GABA and glutamate were co-injected. Overall, the findings suggest that activation of peripheral GABAA receptors in human masticatory muscle produces pain, possibly due to depolarization of the masticatory muscle afferent fibers.

Objectives: The jaw-stretch reflex (JSR) was studied in both patients and healthy participants in order to investigate the possible long-term impact of orthognathic surgery on the motor function of the masticatory system., Design: JSR was measured in patients before surgery (PC), 1year after surgery (PS) and in healthy controls (HC) (N=31 in each group). JSR was evoked by a standardized stretch device and recorded bilaterally from masseter and anterior temporalis muscles using surface electromyography (EMG)., Results: The peak-to-peak amplitude (which was normalized to pre-stimulus EMG activity) of JSRs in PC and PS were significantly smaller than in HC (P<0.001; P<0.001). The onset latency in PS was significantly longer compared with HC (P<0.05). The duration of JSR in PS was significantly longer than in HC and PC (P<0.001; P<0.05)., Conclusion: Patients with dentofacial deformities are characterized by reduced JSR amplitude. The delayed onset and elongated duration of JSR might be potential indicators of a long-term surgical impact on the motor function of the masticatory system., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The aims were to investigate (1) if temporomandibular disorders (TMD) patients with temporomandibular joint (TMJ) pain had different conditioned pain modulation (CPM) compared with healthy subjects and, (2) if clinical pain characteristics influenced CPM. Sixteen TMD pain patients and 16 age-matched healthy subjects were participated. A mechanical conditioning stimulus (CS) was applied to pericranial muscles provoking a pain intensity of 5/10 on a visual analogue scale. Pressure pain thresholds (PPT) and pressure pain tolerance thresholds (PPTol) were assessed at masseter, forearm and painful TMJ (only PPT) before, during, and 20 min after CS. Data were analyzed with ANOVAs. The correlations between CPM effect and ratings of TMD pain intensity on a numerical rating scale (NRS) or the pain duration were calculated (correlation coefficient; R). The relative PPT and PPTol increases (mean for the three assessment sites) during CS were significantly higher than baseline in healthy subjects (43.0 ± 3.6, 33.0 ± 4.0 %; P < 0.001, P < 0.001) but not in the TMD pain patients (4.9 ± 2.7, -1.4 ± 4.1 %; P = 0.492, P = 1.000) with significant differences between groups (P < 0.001). In the patients, the relative PPT changes during CS were not significantly higher than baseline at TMJ (5.3 ± 3.8 %, P = 0.981) and masseter (-2.8 ± 4.8 %, P = 1.000) but significantly higher at forearm (12.3 ± 4.7 %, P = 0.039). No correlation was detected between TMD pain intensity and CPM effect (R = -0.261; P = 0.337) or between pain duration and CPM effect (R = -0.423; P = 0.103) at painful TMJ. These findings indicate that CPM is impaired in TMD pain patients especially at sites with chronic pain but not at pain-free sites and that the clinical pain characteristics do not influence CPM.

Objective: The present study explored the effect of age and gender on trigeminal sensory function and masseteric exteroceptive suppression (ES) reflex responses., Methods: Young healthy men (n = 12) and women (n = 12) (age: 23.5 ± 3.0 years) and older healthy men (n = 12) and women (n = 12) (age: 58.5 ± 5.2 years) participated. Sensory function was assessed on the skin overlying the mental foramen using mechanical stimuli. Surface EMG was recorded from the left masseter muscle to assess ES reflex responses evoked by a magnetic stimulus applied to the skin above the left mental nerve., Results: The older group had significantly higher tactile detection thresholds. Early ES1 was present in all subjects. Onset latency of ES1 was significantly delayed in older subjects. ES2 was present in all young subjects, but only in 5 of the 12 men and 8 of the 12 women in the older group. Significant gender differences were found for sensory and pain thresholds to mechanical stimuli as well as for duration of ES., Conclusions: Ageing affects tactile detection thresholds, onset latency of ES1 responses, and appearance of ES2. The present results indicate that trigeminal sensory function and brainstem reflex responses differ between genders and age groups. These findings may have implications for assessment of craniofacial pain conditions., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Pain in myofascial temporomandibular disorder (TMD) can affect both the masseter and temporalis muscles. Glutamate injection into the masseter muscle evokes pain that is greater in men than in women and this pain is attenuated by co-injection of the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine (10 mmol/L) in men. Animal studies suggested that pain induced by peripheral NMDA receptor activation could differ between the temporalis and masseter muscles and between men and women. The study aims were to investigate differences in glutamate-evoked pain between these muscles and the effectiveness of ketamine to attenuate glutamate-evoked pain in both genders. Pain and mechanical sensitivity were induced in 2 sessions of an experiment in 14 women and 16 men by repeated injections of glutamate (0.5 mol/L) with and without ketamine (20 mmol/L) into the masseter and temporalis muscles. Two injections were applied into the same masseter muscle and 2 injections into the same anterior temporalis muscle at each session. Visual analogue scale (VAS) pain intensities and pain drawing areas were assessed. Glutamate-evoked pain and pain drawing area were significantly greater from the temporalis muscle than from the masseter muscle (P<.02) in both genders. Women reported significantly greater glutamate-evoked masseter muscle pain than men (P<.03). Co-injection of ketamine, at higher dose than previously used, was equally effective in attenuating glutamate-evoked pain from both muscles in both genders (P<.01). The current findings indicate that the characteristics of pain generated by intramuscular injection of glutamate vary for different masticatory muscles and may be partially generated through activation of peripheral NMDA receptors., (Copyright © 2012 International Association for the Study of Pain. All rights reserved.)

The aim of this study was to examine the inhibitory responses in bilateral masseter and temporalis muscle activity when electrical stimulation with short or long duration was applied to six oro-facial locations. The exteroceptive suppression period (ES2) and inhibitory responses were recorded in the surface electromyogram (EMG) of bilateral masseter and temporalis muscles in 16 healthy subjects. Two stimulus durations (1 ms single pulse and 450 ms pulse train) adjusted to a perceived intensity of 7 (distinct painful) on a 0-10 Numerical Rating Scale (NRS) were applied to the following six oro-facial locations on the right side while the subject was biting at 50% of the maximal voluntary contraction: masseter muscle, temporalis muscle, temporomandibular joint, infraorbital nerve, supraorbital nerve, and mental nerve. The stimulus intensity required to reach an NRS score of 7 was significantly lower for 450 ms train stimuli than for 1 ms single stimuli (P<0·001). There were no significant differences in the magnitude of ES2 suppression among the six different locations (P>0·876) for the 1 ms single stimuli. There were significant decreases in Root-Mean-Square-EMG values in the 400-500 ms post-stimulus epoch compared with the pre-stimulus epoch (P<0·023) for 450 ms train stimuli, but there were no significant differences in the magnitude of inhibition among the six different locations (P<0·893). Short- and long-lasting electrical stimulation of various oro-facial locations induces similar bilateral inhibitory effects in the jaw-closing muscles but with different propensity which may reflect the somatotopic organisation of these responses., (© 2010 Blackwell Publishing Ltd.)

Aim: To determine if myofascial temporomandibular disorder (TMD) pain patients have elevated interstitial concentrations of glutamate in the masseter muscle., Methods: Thirteen patients (3 men, 10 women) diagnosed with myofascial TMD pain and 10 (2 men, 8 women) age-matched healthy controls participated in a single microdialysis session. Microdialysis was performed in the patients in the most painful point of the masseter muscle, while in the healthy subjects a standardized point in the muscle was chosen. Two microdialysis samples were collected over 40-minute epochs. A blood sample was also taken for analysis of plasma glutamate concentration. Numeric rating scale (NRS) scores of pain intensity and unpleasantness, McGill Pain Questionnaire data, pain drawing areas, pressure pain thresholds, pressure pain tolerances, maximum voluntary bite force, and maximum voluntary mouth opening were collected as secondary measurements., Results: The median concentration of glutamate in the masseter muscle of the myofascial TMD pain patients (7.5 ± 2.6 ΜM) was significantly higher (P < .023, Mann-Whitney test) than the concentration in healthy controls (0.5 ± 0.4 ΜM). There were, however, no significant correlations between glutamate concentrations in the masseter muscle and NRS pain scores. Plasma concentrations of glutamate were similar in patients and healthy controls., Conclusions: The present study demonstrates a marked increase in interstitial glutamate concentration in the masseter muscle of myofascial TMD pain patients. These novel findings suggest that peripheral glutamate could be involved in the pathophysiology of myofascial TMD pain.

Eccentric jaw exercises has been known to cause muscle soreness but no studies have so far examined to what extent temporal summation mechanisms within the exercised muscles are changed. The purpose of the present study was to investigate the effects of an eccentric biting exercise on the temporal summation, mechanical pressure sensitivity and jaw muscle activity. A total of 15 healthy men participated in a two-session-experiment: In one session, they performed 30 min controlled eccentric jaw exercise and the other session served as a no-exercise control. Soreness sensations at rest and during maximal biting, pressure pain thresholds (PPTs) and electromyographic (EMG) activity during maximal jaw biting were recorded before (baseline), immediately after (Post-task), and 1 day after the exercise (1-day-after). The temporal summation ratio using intra-muscular electrical stimulation of the masseter was investigated at baseline and at 1-day-after. The eccentric jaw exercise was associated with significant increases in soreness sensation and decreased PPTs at Post-task and at 1-day-after. The EMG activity and biting force did not change. The summation ratio was significantly decreased at 1-day-after in both sessions. The present findings demonstrate that eccentric jaw exercise does not induce detectable changes in temporal summation. However, the summation ratio may have clinical utility to differentiate the location of sensitization., (Copyright (c) 2009 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.)

Objectives: The present study compared the perception of electric and magnetic stimuli for reflex appearance threshold (RT) and reflex saturation threshold (RS) of the exteroceptive suppression reflex (ES) in the masseter muscle., Methods: Twelve healthy males and 12 females (age: 24.2+/-3.2 years) participated. The surface EMG was recorded from the left masseter muscle. The stimulus intensities were set as multiple values of the sensory threshold (ST), and were applied to the skin above the left mental nerve. Subjects reported the perceived intensity of the stimulus on a numeric rating scale (NRS) at RT and RS for the early and late ES (ES1 and ES2, respectively)., Results: ES2 had a lower RT and RS compared to ES1 in electric and magnetic stimulation. Significantly lower NRS values at RT and RS were found with painless magnetic stimulation compared to electric stimulation (p<0.01)., Conclusions: In contrast to electrical stimulation, both ES1 and ES2 appeared and saturated with painless magnetic stimuli., Significance: The present results indicate that both ES1 and ES2 have a non-nociceptive origin. Painless magnetic stimuli will be an advantage in ES reflex examinations for various orofacial pain conditions., (Copyright 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

The jaw-stretch reflex is the short-latency response in the jaw-closing muscles after a sudden stretch. The hypothesis whether normalization of the jaw-stretch reflex amplitude with respect to prestimulus electromyographic (EMG) activity will make the amplitude more independent of the location of the electrodes over the masseter muscle was tested. A 5 x 6 electrode grid was used to record the jaw-stretch reflex from 25 sites over the right masseter muscle of 15 healthy men. The results showed that there was a significant site dependency of the prestimulus EMG activity and the reflex amplitude. High cross-correlation coefficients were found between the spatial distribution of mean prestimulus EMG activities and reflex amplitude. When the reflex amplitude was normalized with respect to the prestimulus EMG activity, no site dependency was found. In conclusion, normalization of the jaw-stretch reflex amplitude by the prestimulus EMG activity strongly reduces its spatial dependency.

Objective: Examine the effect of stimulus duration, intensity and level of muscle contraction on the inhibitory responses evoked by electrical stimuli in human jaw-closing muscles applied to the right mental nerve., Design: The inhibitory jaw-reflexes, short-latency (ES1) and long-latency (ES2), were recorded in the surface electromyogram (EMG) of masseter and temporalis muscles in 16 healthy subjects. Three stimulus durations (1ms single square-wave pulse, 10 and 450ms square-wave pulse train), two stimulus intensities adjusted to perceived intensity of 3 (non-painful) and 7 (distinct painful) on a 0-10 verbal rating scale were applied to the right mental nerve while the subject was biting at 25% and 50% of the maximal voluntary contraction (MVC)., Results: The magnitude of suppression in the ES2 evoked by 1 and 10ms stimuli was dependent on stimulus intensity (P<0.002 and P<0.001, respectively) but not contraction level. However, ES1 could not be observed in most of the recordings. There were significant decreases evoked by the 450ms stimuli in RMS-EMG values in the 400-500ms compared with the pre-stimulus interval (P<0.001) which was dependent on contraction level (P<0.01) but not on stimulus intensity (P=0.486)., Conclusions: The present results suggest that the ES2 reflex response is associated with the duration of the electrical stimuli, the intensity level but not the contraction level. In contrast, the inhibitory effects of ultra-long stimuli (450ms) are not specifically related to the intensity level suggesting that this is a non-nociceptive response.

Nociceptive substances, injected into the masseter muscle, induce pain and facilitate the jaw-stretch reflex. It is hypothesized that intense chewing would provoke similar effects. Fourteen men performed 20 bouts of 5-minute chewing. After each bout, 20 min and 24 hrs after the exercise, muscle fatigue and pain scores and the normalized reflex amplitude from the left masseter muscle were recorded. Before, 20 min, and 24 hrs after the exercise, signs of temporomandibular disorders and pressure-pain thresholds of the masticatory muscles were also recorded. Fatigue and pain scores had increased during the exercise (P < 0.001), but the reflex amplitude did not (P = 0.123). Twenty minutes after the exercises, 12 participants showed signs of myofascial pain or arthralgia. Pressure-pain thresholds were decreased after 20 min (P = 0.009) and 24 hrs (P = 0.049). Intense chewing can induce fatigue, pain, and decreased pressure-pain thresholds in the masticatory muscles, without concomitant changes in the jaw-stretch reflex amplitude.

To compare the jaw-stretch reflex and pressure pain thresholds (PPT) in chronic tension-type headache (CTTH) patients and healthy controls, 30 patients (15 male and 15 female) and 30 age- and sex-matched healthy subjects were investigated. Stretch reflexes were recorded in the temporalis and masseter muscles and PPT was determined in the anterior temporalis, splenius capitis and masseter muscles. The results showed that the amplitude of the stretch reflex in CTTH patients was higher compared with control subjects (P < 0.045), and higher in women compared with men in the right and left anterior temporalis muscles (P < 0.009). There were no differences in the PPT value between CTTH and control subjects (P > 0.509), whereas women showed significantly lower PPT measurements (P < 0.046). The results demonstrated a facilitation of the stretch reflex pathways in CTTH patients that is unrelated to measures of pericranial sensitivity.

Purpose: The purpose of this study was to characterize the relation between stimulus intensity, masseteric exteroceptive suppression (ES), and sensory perception as a possible quantitative or qualitative tool in the diagnosis of the masticatory system for prosthodontic treatment., Methods: From 12 males and 12 females (22-41 years), surface EMG was recorded from the left masseter muscle. Visual feedback allowed the subjects to maintain a constant clenching level of 30% maximal voluntary contraction. Thirteen fixed stimulus intensities from 5 to 35 mA in 2.5 mA increments were applied at random. A computer program calculated the duration of ES, based on the 50% level of the mean pre-stimulus EMG. The stimulation intensity at which early (ES1) or late (ES2) exteroceptive suppressions appeared first and at which subjects answered as being painful were defined as the reflex threshold (RT1 or RT2) and pain threshold (PT), respectively. The relation between sensory perception and ES was evaluated using stimulus-response (S-R) curve analysis., Results: Significant differences were found between PT and RT1, and between RT1 and RT2 (P<0.001). After S-R curve analysis, the maximum duration of ES1 and ES2 was estimated at 9.6 ms and 33.5 ms, and appearance was rated as 6.2 and 4.0 on numeric rating scale (NRS), saturation was 7.6 and 6.9, and slope was 7.0 and 11.2, respectively., Conclusions: All parameters for changes in ES following increasing incremental stimulus intensity could be analyzed. The construction of S-R curves in relation to sensory perception and ES parameters characterized the difference between ES1 and ES2.

Aim: To investigate effect of capsaicin-evoked masseter-muscle pain on intramuscular blood-flow (BF) at rest and during contractions., Methods: Eight healthy men (22-31 years) participated. BF was measured with Laser Doppler (Moor Instruments, UK) using a single-fibre probe inserted into the right masseter. Three BF probes were attached to the skin above right and left masseter and the right-middle finger. Subjects performed 30 s isometric contractions at 5%, 15%, and 25% of maximal voluntary contraction. After the contractions, capsaicin (0.1 mL, 100 microg/mL) was injected into the right masseter close to the fibre probe. When the pain sensation had disappeared, the series of submaximal contractions were repeated. BF data were sampled continuously, processed in 10s bins, and analyzed with repeated-measures ANOVAs., Results: Intramuscular BF significantly increased immediately after capsaicin injection (P < 0.050) and rapidly (30 s) decreased to pre-injection values. A significant increase in cutaneous BF above the right masseter was observed (P < 0.050) and lasted for 10 min, while a significant BF decrease in the finger (P < 0.050) was observed. The contractions were associated with increases in intramuscular BF before and after the injection (P < 0.022) and the contraction levels were also associated with increase in intramuscular BF before injection (P=0.008) but not after injection (P = 0.314)., Conclusions: This study demonstrated BF increased by muscle contraction but failed to show effects of contraction levels on BF in a muscle exposed to nociceptive stimuli. Neurogenic inflammation in muscles could possibly be mediated via antidromical effects and local release of vasoactive substances. The decreased BF in the finger could be due to involvement of central regulatory mechanisms.

Objective: To investigate the effects of soreness evoked by eccentric jaw exercises on two types of brainstem reflexes: the short-latency stretch reflex and the longer-latency exteroceptive suppression (ES), and to test for possible relationships between magnitude of soreness and reflex responses., Methods: The brainstem reflexes of jaw-closing muscles were recorded before (Baseline), immediately after (Post-task), and 1 day after (1-day-after) a 30-min eccentric exercise in 15 healthy men. All subjects participated in a control session without exercise., Results: Soreness sensations at rest and during maximum biting were significantly elevated until 1-day-after the eccentric exercise (P<0.014). The ES responses tended to be increased (more inhibition) at Post-task and 1-day-after. There was a significant correlation between the ES response and the soreness sensation during maximum biting (P<0.04). The jaw-stretch reflex did not show significant change after the eccentric exercise., Conclusions: Muscle soreness associated with eccentric jaw exercises has a differential impact on the jaw-stretch reflex and the ES response., Significance: Experimentally induced acute muscle pain has previously been shown to influence both the ES and the jaw-stretch reflex, thus, different types of muscle pain and symptoms can be speculated to have different effects on a variety of brainstem reflexes.

Objective: This study examined the somatosensory function in the trigeminal region and quantitative measures of the exteroceptive suppression (ES) period in the masseteric EMG, in relation to a psychological evaluation., Methods: The ES in the surface EMG was recorded from the left masseter muscle in 12 men and 12 women. The stimulation intensity at which the ES appeared first and the lowest intensity at which the subjects reported it to be painful were defined as the electrical reflex threshold and electrical pain threshold, respectively. Three experimental sessions were scheduled. The state and trait anxiety inventory was used to evaluate the psychological status., Results: The electrical reflex threshold significantly decreased (p<0.01), and the electrical pain threshold significantly increased (p<0.01) over the sessions in line with the effect on the state anxiety inventory (p<0.05)., Conclusions: The present results illustrate that reflex parameters and electrical pain thresholds are associated with state anxiety. Possibly, habituation or decreased fear from the experimental set-up may play a role., Significance: This is important when electrophysiology or quantitative sensory testing is used to assess trigeminal nociception, e.g., in orofacial pain conditions.

Objective: Compare pain-related measures and psychosocial variables between glutamate-evoked jaw muscle pain in healthy subjects (HS) and patients with persistent myofascial temporomandibular disorder (TMD) pain., Design: Forty-seven female HS and 10 female patients with persistent myofascial TMD pain participated. The HS received an injection of glutamate into the masseter muscle to model persistent myofascial TMD pain. Participants filled out a coping strategies questionnaire (CSQ), the symptom checklist 90 (SCL-90) and McGill pain questionnaire (MPQ). Pain intensity was assessed on an electronic visual analogue scale (VAS). Pain-drawing areas, numerical rating scale (NRS) scores of unpleasantness, pressure pain thresholds (PPTs) and pressure pain tolerance (PPTOL) were measured. Unpaired t-tests and correlation tests were used for analyses., Results: The groups were significantly different when comparing the CSQ scores of control, decrease, diverting attention, increase of behavioural activities and somatization. The peak VAS pain, NRS of unpleasantness and MPQ scores were not significantly different between groups, but PPT and PPTOL were significantly lower in the TMD patients. Significant positive correlations were found in the TMD patients between peak VAS pain and CSQ catastrophizing score and SCL-90 somatization. The scores of PPTs and PPTOLs, in patients showed positive correlations with CSQ reinterpreting pain sensations scores and PPTs correlated with CSQ praying/hoping scores., Conclusions: Glutamate-evoked pain responses in HS and persistent myofascial TMD pain have similar sensory-discriminative and affective-unpleasantness components but differ in psychosocial features. This study suggests that experimental designs based on glutamate injection into muscle can provide an appropriate model for elucidating persistent myofascial pain conditions.

Temporomandibular disorders (TMDs) are associated with perturbation of proprioceptive and nociceptive function. Recent studies have shown that injection of the neurotrophic protein nerve growth factor (NGF) into the masseter muscle causes sensitization to mechanical pressure stimuli; however, it is not clear if vibration sense and jaw stretch reflexes as measures of proprioceptive function as well as glutamate-evoked pain are also altered. We tested the hypothesis that NGF-induced mechanical sensitization would be associated with changes in vibration sense and stretch reflex sensitivity as well as facilitation of glutamate-evoked pain responses. A double-blind, randomized and placebo-controlled study was conducted on 14 healthy men. In one session subjects received an injection of NGF (5 microg in 0.2 ml) into the masseter muscle and in a control session an injection of buffered isotonic saline (0.9%, 0.2 ml). Subjects assessed their pain intensity on a 0-10 cm visual analogue scale (VAS) for 15 min after the injections. Pressure pain thresholds (PPT), vibration sense and jaw stretch reflexes were recorded at baseline and 1, 2, 3 and 24 h post-injection. The sensitivity to injections of glutamate into the masseter muscle (1 M, 0.2 ml) was assessed after 24 h. ANOVAs were used to assess significant differences. NGF did not cause more pain than isotonic saline, but significantly reduced PPTs 1, 2, 3 and 24 h post-injection (P < 0.001) whereas isotonic saline had no effects on PPTs (P = 0.583). The injection of glutamate after 24 h was associated with reduced PPTs in both sessions, but the PPTs remained lower in the NGF pretreated masseter than in the control masseter (P < 0.001). Ratings of vibratory stimuli and the normalized amplitude of the jaw stretch reflex were not affected by the NGF-induced sensitization; however, after glutamate injection a significant increase in the stretch reflex was observed in the injected masseter muscle in both sessions (P = 0.002). There were no significant differences in the perceived pain intensity of the glutamate injection between the masseter muscle pretreated with NGF or control (P > 0.414), although the glutamate-evoked pain drawing areas were larger for the NGF-pretreated masseter muscle (P = 0.009). In conclusion, this study confirms that masseter muscle injection of NGF is associated with a distinct and prolonged sensitization to mechanical stimuli, but without an effect on large-diameter mechanoreceptive and the muscle spindle afferents. Additional challenge of the NGF pretreated muscle with glutamate did not indicate a conspicuous sensitization to noxious chemical stimuli. These findings are discussed in terms of the concept of "proprioceptive allodynia".

There is evidence that elevated tissue concentrations of glutamate may contribute to pain and sensitivity in certain musculoskeletal pain conditions. In the present study, the food additive monosodium glutamate (MSG) was injected intravenously into rats to determine whether it could significantly elevate interstitial concentrations of glutamate in the masseter muscle and whether MSG administration could excite and/or sensitize slowly conducting masseter afferent fibers through N-methyl-D-aspartate (NMDA) receptor activation. The interstitial concentration of glutamate after systemic injection of isotonic phosphate-buffered saline (control) or MSG (10 and 50mg/kg) was measured with a glutamate-selective biosensor. The pre-injection baseline interstitial concentration of glutamate in the rat masseter muscle was 24+/-11 microM. Peak interstitial concentration after injection of 50mg/kg MSG was 63+/-18 microM and remained elevated above baseline for approximately 18 min. In vivo single unit recording experiments were undertaken to assess the effect of MSG (50mg/kg) on masseter afferent fibers. Injection of MSG evoked a brief discharge in one afferent fiber, and significantly decreased ( approximately 25%) the average afferent mechanical threshold (n=10) during the first 5 min after injection of MSG. Intravenous injection of ketamine (1mg/kg), 5 min prior to MSG, prevented the MSG-induced decreases in the mechanical threshold of masseter afferent fibers. The present results indicate that a 2- to 3-fold elevation in interstitial glutamate levels in the masseter muscle is sufficient to excite and induce afferent mechanical sensitization through NMDA receptor activation. These findings suggest that modest elevations of interstitial glutamate concentration could alter musculoskeletal pain sensitivity in humans.

In the present study, the hypothesis that sex-related differences in glutamate-evoked rat masseter muscle afferent discharge may result from estrogen-related modulation of peripheral N-methyl-d-aspartate (NMDA) receptor activity and/or expression was tested by examining afferent fiber discharge in response to masseter injection of NMDA and the expression of NR2A/B subunits by masseter ganglion neurons in male and female rats. The results showed that injection of NMDA into the masseter muscle evoked discharges in putative mechanonociceptive afferent fibers and increased blood pressure that was concentration-dependent, however, a systemic action of NMDA appeared responsible for increased blood pressure. NMDA-evoked afferent discharge was significantly greater in female than in male rats, was positively correlated with plasma estrogen levels in females and was significantly greater in ovariectomized female rats treated with a high dose (5 mug/day) compared with a low dose (0.5 mug/day) of estrogen. Pre-treatment of high dose estrogen-treated-ovariectomized female rats with the Src tyrosine kinase inhibitor PP2 did not affect NMDA-evoked afferent discharge. NMDA-evoked afferent discharge was attenuated by the antagonists ketamine and ifenprodil, which is selective for NR2B containing NMDA receptors. Fewer masseter ganglion neurons expressed the NR2A (16%) subunit as compared with the NR2B subunit (38%), which was expressed at higher frequencies in intact female (46%) and high dose estrogen-treated ovariectomized female (60%) rats than in male (31%) rats. Taken together, these results suggest that sex-related differences in NMDA-evoked masseter afferent discharge are due, at least in part, to an estrogen-mediated increase in expression of peripheral NMDA receptors by masseter ganglion neurons in female rats.

The present study evaluated the reproducibility of the late exteroceptive suppression period (ES2) and of pain perception. The surface electro-myogram (EMG) was recorded from the left masseter muscle in 12 males and 12 females (22-31 year). Thirteen fixed stimulus intensities from 5 to 25 mA with 2.5 mA intervals were applied at random to the left mental area, and stimulus-response (S-R) curves were built for each subject. The first stimulation intensity at which the ES2 appeared was defined the reflex threshold, while the lowest stimulus intensity the subjects scored as painful, was called the pain threshold. Using the S-R curves, the other reflex parameters (appearance level, saturation level, slope from appearance to saturation, maximum duration of ES2, and maximum suppression degree) were also determined. Two measurement sessions were scheduled. Both the reflex and the pain sensation appeared at significantly lower stimulus intensity in females than males (P < 0.05). The reflex threshold, the reflex appearance and saturation level showed a significant decrease from the first to second session (P < 0.05), while the pain threshold was significantly higher during the second session (P < 0.01). By contrast, a good reproducibility was found for the maximum duration and suppression degree of ES2. Consequently, if S-R curves would be used to study the relation between the ES2 parameters and stimulus intensity in normal subjects for their applicability in clinical conditions, maximum duration and maximum suppression degree should be focused upon, in order to avoid session and gender effects as confounding factors.

The purpose of the present study was to determine whether glutamate-induced mechanical sensitization of the masseter muscle in human volunteers involves activation of peripheral N-methyl-D-aspartate (NMDA) receptors. Healthy male volunteers (n=18) participated in this randomized, two-session study. During each session, the volunteers received two injections into the right masseter muscle. An initial injection of glutamate (1 M, 0.2 ml) alone was followed 30 min later by a second injection of glutamate alone or glutamate combined with ketamine (10 mM). Pressure pain threshold (PPT) was assessed over the right masseter muscle at and 2 cm above the injection site, as well as over the right temporalis muscle and left masseter muscle prior to the first injection. The PPT was reassessed at all four sites every 5 min from 10 to 30 min after the second injection and once again 60 min after the second injection. Glutamate-evoked muscle pain, pain area and the sensory pain response index of the McGill pain questionnaire were all significantly reduced by co-injection of ketamine. The mean PPT values were significantly decreased by approximately 10%, 10, 15 and 25 min after injection of glutamate, but only over the site of injection. Co-injection of ketamine with glutamate also completely blocked the glutamate-induced mechanical sensitization 15 min post-injection as compared with glutamate alone. The lack of spread of mechanical sensitization outside the area of glutamate injection is consistent with the view that glutamate-induced mechanical sensitization results from a peripheral mechanism. The attenuation of glutamate-induced mechanical sensitization by ketamine suggests that this effect is mediated, in part, through activation of peripheral NMDA receptors.

The present study documented quantitative changes in the duration and the depth of the exteroceptive suppression (ES) period in the masseteric electromyogram (EMG) using stimulus-response (SR) curves. From six males and six females (20-41 years), the surface masseteric EMG was recorded bilaterally. Visual feedback from the left masseter muscle (MM) allowed a constant clenching level of 30% or 50% maximal voluntary contraction (MVC). Automatic triggering of the stimulus to the left mental nerve occurred when the background EMG remained constant. Eight to twelve stimulus intensities (range, 0-40 mA) were determined based on the subjects' sensory threshold (T). The late ES (ES2) occurred consistently and could be analyzed using SR curves. ES2 in the right MM appeared at 7.3+/-3.1T at 30% MVC, while it was significantly decreased to 5.2+/-2.2T at 50% MVC (P<0.05). The depth of ES2 suppression in the left MM was 69.7+/-5.7% at 30% MVC, and this increased significantly to 76.6+/-5.5% at 50% MVC (P<0.05). In addition, the depth of ES2 suppression in the left MM was significantly higher than that in the right MM at 50% MVC (70.0+/-7.4%, P<0.05). Consequently, it was confirmed that both the appearance and depth of ES may be affected by the level of background EMG. More importantly, the use of multiple stimulation intensities allowed development of reliable SR curves. These SR curves may be used to determine inter-individual differences in ES.

Objective: Use of brain stem reflexes in the assessment of orofacial function requires insight into the influence of demographic factors such as gender. The aim of this study was to characterize possible gender differences in the relation between quantitative measures of the masseteric exteroceptive suppression (ES) reflex response and pain perception evoked by incrementally increasing electrical stimulation., Methods: In 12 men and 12 women, the surface electromyogram was recorded from the left masseter muscle. Thirteen fixed stimulus intensities from 5 to 35 mA at 2.5 mA increments were applied to the skin above the left mental nerve. The stimulation intensity at which the late ES appeared first and the first intensity at which the subjects reported the stimulus intensity to be painful were defined as the reflex threshold (RT) and pain threshold (PT), respectively. Furthermore, data were analyzed using stimulus-response curves, and the reflex appearance levels (RAL), the saturation level, the slope from appearance to saturation of the reflex (SLP), and the pain appearance level (PAL) were determined., Results: The PT was equal to or higher than the RT in 9 of the 12 men, but only in 4 of the 12 women. Further, women had significantly lower PAL, RAL, and SLP (12.7 +/- 0.8, 12.9 +/- 1.4, and 3.0 +/- 0.9 mA, respectively) compared to men (20.3 +/- 1.6 mA, 16.7 +/- 1.1 T, and 4.1 +/- 0.4, respectively) (P < 0.05)., Conclusions: The present results document that women have a lower reflex threshold and pain threshold to cutaneous electrical stimulation than men., Significance: These findings suggest that gender differences may exist in the sensory-motor integration of primary afferent input from the orofacial region and that these differences should be considered in the design of future reflex studies.

Aims: To document and compare the intensity, localization, and quality of pain evoked by glutamate injections into the human masseter or splenius muscles and to determine the effect of glutamate-evoked pain on the pressure pain thresholds (PPTs) in both jaw and neck muscles., Methods: Twenty-six healthy men were given painful injections of glutamate (1.0 mol/L) and control injections of isotonic saline (0.165 mol/L) into the masseter and splenius muscles. The subjects rated the perceived intensity of pain on a visual analog scale (VAS), drew the area of the pain on maps of the face and neck, and filled out a Danish version of the McGill Pain Questionnaire (MPQ). PPTs were used to assess the sensitivity of the masseter and splenius muscles to mechanical stimuli (n = 11)., Results: Glutamate injection into the masseter or splenius evoked pain lasting almost 10 minutes. Peak pain intensity usually occurred within 2 minutes of the injection, and VAS scores of peak pain were significantly higher for the masseter muscle compared with the splenius muscle (paired t test, P = .003). The pain area from the masseter injections did not extend into the neck region, although in some subjects the pain from the neck region extended into the temporal region. There were no significant relationships between the area of perceived pain and the VAS pain scores (Pearson correlation, P > .297). Glutamate-evoked pain in either the masseter or splenius muscles was associated with significant decreases in masseter or splenius PPTs, respectively (2-wayANOVAs, P < .016). Isometric saline injections were almost pain-free and caused no PPT changes., Conclusion: The data suggest that the masseter muscle is more sensitive to glutamate injections and mechanical stimuli than the splenius muscle. The relatively limited overlap between the sensory manifestations of pain from masseter and splenius muscles may have potential implications for diagnosis and management of myofascial pain complaints in the craniofacial and neck region.

Objective: Muscle pain is known to influence muscle activity but the details of its effects on the mechanical properties of single motor units (SMU) have not been described. We have recently reported a decreased firing rate of SMU in the human masseter muscle during painful contractions with a constant force output. Force output can be modulated by the SMU discharge rate in relation to the contractile properties of SMU. Therefore, the objective of the present study was to measure the mechanical properties of SMU in the masseter to clarify the mechanism which underlies the decrease in SMU firing rate during jaw-muscle pain., Methods: A spike-triggered averaging (STA) technique was used to determine the mechanical properties of low-threshold SMU in the masseter muscle recorded with fine wire electrodes during a voluntary isometric contraction. The twitch amplitude, contraction time, and half-relaxation time were determined from the averaged force records before and during experimental jaw-muscle pain induced by injection of 0.2 ml (100 microg/ml) capsaicin in 8 healthy subjects. Injections of 0.2 ml isotonic saline served as a non-painful control in 11 healthy subjects., Results: The twitch amplitude was significantly increased during capsaicin-evoked muscle pain (P<0.001) without significant changes of half-relaxation time and contraction time. No significant changes in SMU twitch properties were observed during the control injections., Conclusions: Potentiation of twitch force could be a possible compensatory mechanism to maintain a constant force output during painful isometric contractions when SMU firing decreases. This finding therefore provides new information on the adaptation of motor function by muscle pain.

Peripheral N-methyl-d-aspartate (NMDA) receptors are found in deep tissues and may play a role in deep tissue pain. Injection of the endogenous NMDA receptor agonist glutamate into the masseter muscle excites deep craniofacial afferent fibers in rats and evokes pain in human subjects. It is not clear whether peripheral NMDA receptors play a role in these effects of glutamate. Accordingly, the effect of NMDA on afferent activity as well as the effect of locally administered NMDA receptor antagonists on glutamate-evoked afferent discharges in acutely anesthetized rats and muscle pain in human subjects was examined. Injection of NMDA into the masseter muscle evoked afferent discharges in a concentration-related manner. It was found that the NMDA receptor antagonists 2-amino-5-phosphonvalerate (APV, 10 mM), ketamine (10 mM), and dextromethorphan (40 mM) significantly decreased glutamate-evoked afferent discharges. The effects of APV and ketamine, but not dextromethorphan, were selective for glutamate-evoked afferent discharges and did not affect hypertonic saline-evoked afferent discharges. In human experiments, it was found that 10 mM ketamine decreased glutamate-evoked muscle pain but had no effect on hypertonic saline-evoked muscle pain. These results indicate that injection of glutamate into the masseter muscle evokes afferent discharges in rats and muscle pain in humans in part through activation of peripheral NMDA receptors. It is conceivable that activation of peripheral NMDA receptors may contribute to masticatory muscle pain and that peripherally acting NMDA receptor antagonists could prove to be effective analgesics for this type of pain.

Aims: To compare jaw-stretch reflex responses in male and female subjects and to determine whether injection of glutamate into the masseter muscle facilitates these responses in both sexes., Methods: Jaw-stretch reflex responses were evoked with a muscle stretcher, and pain intensity was scored by 11 men and 13 women before and after the injection of glutamate (1.0 mol/L, 0.2 ml) into the masseter muscle. The subjects rated glutamate-evoked pain intensity on a visual analog scale., Results: Baseline jaw-stretch reflex responses were larger and glutamate injections into the masseter muscle were significantly more painful in women than in men, however, glutamate significantly facilitated jaw-stretch reflex responses in men but not in women., Conclusion: These results suggest that there is a significant sex-related difference in human jaw-stretch reflex responses and their modulation by painful stimuli. Since one possible function of facilitated jaw-stretch reflex responses during jaw muscle pain may be to reduce jaw mobility and thus protect against further exacerbation of an existing injury, the finding of a sex-related difference in modulation of jaw-stretch reflex responses may prove to be important in clarifying why the prevalence of temporomandibular disorders is greater in women than in men.

Nerve growth factor (NGF) is a neurotrophic protein with a pivotal role in development and maintenance of the nervous system on one side and inflammatory and neuropathic pain states on the other. NGF causes clear signs of behavioral hyperalgesia in animal models and following intradermal and systemic administration in humans. The present double-blinded, placebo-controlled study was designed to test quantitatively the effect and duration (1h, 1, 7, 14, 21 and 28 days) of NGF (5 microg in 0.2 ml) injected into the masseter muscle. Pressure pain thresholds (PPT) and pressure tolerance thresholds (PTOL) were used as indices of mechanical allodynia and hyperalgesia in the jaw-closing muscles. In addition, perceived pain intensity was assessed by the subjects on a 0-10 numerical rating scale (NRS) with the jaw at rest and in relation to various oral functions (chewing, yawning, talking, swallowing, drinking and smiling). Repeated measures analysis of variance (ANOVA) was used to test for significant effects. Injection of NGF into the masseter muscle was associated with significantly reduced PPT for 7 days (ANOVA: P<0.001) and PTOL for 1 day (P<0.001). Buffered isotonic saline injections into the masseter muscle also significantly lowered the PPT after 1 day but to a significantly smaller extent than the NGF injections (P<0.001) and isotonic saline had no significant effects on PTOL. In contrast, assessment of PPT and PTOL in the non-injected temporalis muscles demonstrated a significant increase after 14-28 days (P<0.001), which may have reflected an adaptation to the test procedure. NRS scores of chewing and yawning were significantly increased for 7 days following NGF injection (P<0.001). Systemic adverse effects were noted in one subject who reported fever and slight discomfort about 8h after the NGF injection. In conclusion, this is the first study to show that injection of NGF into the human masseter muscle causes local signs of mechanical allodynia and hyperalgesia that persist for at least 7 days as well as pain during strenuous jaw movement. The present pain model is safe and may be used to gain further insight into the neurobiological mechanisms of muscle pain and sensitization.

The present study examined the effect of peripheral administration of the excitatory amino acid (EAA) glutamate on the intensity of perceived pain and pressure pain thresholds (PPTs) in healthy young women (n=17) and men (n=18). Two injections separated by 25 min of 0.2 ml, 1.0M glutamate into the masseter muscle produced significantly higher scores of pain on 0-10 cm visual analogue scales (VAS) in women than in men (analysis of variance, ANOVA: P<0.001). There was no significant difference between the VAS scores for the first and the second injections in either men or women. The PPTs determined in the masseter muscle were significantly reduced following the first injection and further significantly reduced after the second injection (ANOVA: P<0.001). Furthermore, the PPTs were reduced to a similar extent in both women and men (maximum 44-56%), suggesting that gender did not influence the process of sensitization. There were no significant difference in VAS scores or PPTs between women taking oral contraceptives (n=9) and those who did not (n=8) (ANOVAs: P=0.709, P=0.153). It is concluded that the VAS scores produced by intramuscular administration of 1.0M glutamate may reflect a gender-dependent activation of nociceptive pathways which, in part, may be mediated through peripheral EAA receptors. The reduction of PPTs in the masseter muscle following administration of glutamate in a concentration of 1.0M may reflect allodynia to mechanical stimuli. This process of sensitization was not gender-dependent. The present results suggest that injection of 1.0M glutamate into the masseter muscle may provide a useful experimental method to test sensitization and efficacy of peripheral EAA receptor antagonists in human subjects.

The pathophysiology of painful temporomandibular disorders is not fully understood, but evidence suggests that muscle pain modulates motor function in characteristic ways. This study tested the hypothesis that activation of nociceptive muscle afferent fibers would be linked to an increased excitability of the human jaw-stretch reflex and whether this process would be sensitive to length and velocity of the stretch. Capsaicin (10 micro g) was injected into the masseter muscle to induce pain in 11 healthy volunteers. Short-latency reflex responses were evoked in the masseter and temporalis muscles by a stretch device with different velocities and displacements before, during, and after the pain. The normalized reflex amplitude increased with an increase in velocity at a given displacement, but remained constant with different displacements at a given velocity. The normalized reflex amplitude was significantly higher during pain, but only at faster stretches in the painful muscle. Increased sensitivity of the fusimotor system during acute muscle pain could be one likely mechanism to explain the findings.

Objectives: The relationship between the masseter inhibitory reflex (MIR) and nociceptive processing in the trigeminal region was studied in 10 healthy subjects. Based on the known increase in perceived sensory intensity following repetitive stimulation of the nociceptive system, we examined the hypothesis that the MIR reflects noxious activity in the trigeminal system by determining the possible relation between changes in MIR and perceived sensory intensity., Methods: The MIR was quantitated and compared with psychophysical measures following repetitive peri-oral electrical stimulation (5 square wave pulses of 0.5ms repeated at 2Hz). In addition to the early (ES1) and late (ES2) periods of exteroceptive suppression, two periods with apparent excitation could be distinguished from the background electromyografical activity: (a) the inter-suppression period (ISP) between the ES1 and the ES2, and (b) the post-suppression period (PSP) after the ES2. A computer algorithm was used to detect and quantitate ES1, ES2, ISP, and PSP. The response variables were (a) onset latencies and (b) magnitudes of suppression (ES1 and ES2) and excitation (ISP and PSP)., Results: Consistent reduction of the magnitude of ES2 suppression in response to repetitive stimuli was observed below as well as above the pain detection threshold., Conclusions: The observed reduction of the magnitude of ES2 suppression is not specifically related to nociceptive processing. Habituation or net inhibitory effects on inhibitory pre-motor neurones (i.e. disinhibition) are possible mechanisms for the observed reduction of the magnitude of ES2 suppression after repetitive stimulation.

In rats, intradermal or intraarticular injection of glutamate or selective excitatory amino acid receptor agonists acting at peripheral excitatory amino acid receptors can decrease the intensity of mechanical stimulation required to evoke nocifensive behaviors, an indication of hyperalgesia. Since excitatory amino acid receptors have been found on the terminal ends of cutaneous primary afferent fibers, it has been suggested that increased tissue glutamate levels may have a direct sensitizing effect on primary afferent fibers, in particular skin nociceptors. However, less is known about the effects of glutamate on deep tissue afferent fibers. In the present study, a series of experiments were undertaken to investigate the effect of intramuscular injection of glutamate on the excitability and mechanical threshold of masseter muscle afferent fibers in anesthetized rats of both sexes. Injection of 1.0 M, but not 0.1 M glutamate evoked masseter muscle afferent activity that was significantly greater than that evoked by isotonic saline. The mechanical threshold of masseter muscle afferent fibers, which was assessed with a Von Frey hair, was reduced by approximately 50% for a period of 30 min after injection of 1.0 M glutamate, but was unaffected by injections of 0.1 M glutamate or isotonic saline. Injection of 25% dextrose, which has the same osmotic strength as 1.0 M glutamate, did not evoke significant activity in or decrease the mechanical threshold of masseter muscle afferent fibers. Magnetic resonance imaging experiments confirmed that injection of 25% dextrose and 1.0 M glutamate produced similar edema volumes in the masseter muscle tissue. Co-injection of 0.1 M kynurenate, an excitatory amino acid receptor antagonist, and 1.0 M glutamate attenuated glutamate-evoked afferent activity and prevented glutamate-induced mechanical sensitization. When male and female rats were compared, no difference in the baseline mechanical threshold or in the magnitude of glutamate-induced mechanical sensitization of masseter muscle afferent fibers was observed; however, the afferent fiber activity evoked by injection of 1.0 M glutamate into the masseter muscle was greater in female rats. The results of the present experiments show that intramuscular injection of 1.0 M glutamate excites and sensitizes rat masseter muscle afferent fibers through activation of peripheral excitatory amino acid receptors and that glutamate-evoked afferent fiber activity, but not sensitization, is greater in female than male rats.

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 microl) 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 microl, 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.

Aims: Sleep bruxism, which is a form of orofacial motor activity (OMA), and jaw muscle pain and soreness have for a long time been thought to be mutually linked. The aim of this study was to investigate the effect of clinical and experimental jaw muscle pain and soreness on sleep OMA., Methods: Twelve healthy subjects aged 21 to 31 years old participated in this study. All of them were aware of signs or symptoms of sleep OMA and were subdivided into a group with clinical pain complaints (n = 5) and a group without pain (n = 7). All subjects slept in the laboratory for 3 consecutive nights, including a habituation night, a baseline night, and an experimental night. Electroencephalographic (EEG) activity and electromyographic (EMG) activity from the masseter muscles were recorded during sleep. On the experimental night, before sleep, all subjects received an injection of capsaicin (0.1 mL, 100 micrograms/mL) into the masseter muscle that had demonstrated the most EMG activity during the previous recordings. The OMA events and episodes were quantified and were compared between the baseline night and the experimental night. Every evening and morning during the study period, pain intensity, unpleasantness, and soreness were scored by the subjects on a visual analog scale (VAS), and pain detection thresholds (PDTs) in the masseter muscles and maximal voluntary occlusal force (MVOF) were also measured., Results: Pre-sleep injection of capsaicin did not cause significant differences between groups in peak pain intensity on the VAS. The PDT and MVOF did not show any significant differences between groups, injection and non-injection sides, or baseline and experimental nights and mornings. The number of EMG episodes/hour sleep, the number of bursts/hour sleep, and total area of all bursts and episodes during the baseline night were significantly higher in the subjects without pain than in the subjects with pain. However, the capsaicin injection did not cause any significant changes in these parameters., Conclusion: This study suggests that an acute pre-sleep painful stimulus does not have any effect on OMA during sleep, but the study extends previous findings that clinical jaw muscle pain and soreness are associated with less EMG activity in the masticatory muscles.

It has recently been shown that a slow stretch evokes a short-latency (probably monosynaptic) and a long-latency (polysynaptic) reflex response in human jaw-closing muscles. The effect of nociceptive muscle input on the fusimotor system has not been investigated in detail. In order to investigate the effect of sustained muscle pain on the jaw stretch reflex, two main experiments were performed. Stretch reflex responses were evoked in the masseter and temporalis muscles by slow stretches (1-mm displacement, 40-ms ramp time) before, during and 15 min after a period of experimentally induced muscle pain. In experiment I, a dose of 1.0 M hypertonic or 154 mM isotonic (control) saline was infused in random order into the left masseter for up to 15 min (n=12). The level of excitation of the left masseter at 15% maximal voluntary contraction was controlled by visual feedback of the surface EMG (sEMG). In experiment II, a dose of 1.0 M saline was infused into the left masseter but with feedback from the sEMG of the right masseter (n=12). In a control experiment, both sEMG and intramuscular EMG (imEMG) were recorded from the left and right masseters; the feedback was from imEMG of the left masseter (n=12). The early (onset: 9--10 ms) and late (duration from 25 to 40 ms) reflex components were recorded and analysed in all experiments. Infusion of 1.0 M saline caused moderate pain (mean score on a Visual Analogue Pain Scale: 4.9--5.0 cm). The peak-to-peak amplitude of the early reflex component in the painful masseter normalized to the pre-stimulus EMG activity was significantly higher during the pain than the pre- and post-infusion conditions in all experiments. The normalized area of the late reflex component in the painful masseter was significantly larger than in the pre-infusion condition in all experiments. Isotonic saline had no significant effect on the jaw stretch reflexes. These results indicate that experimental jaw-muscle pain in humans facilitates the early as well as the late component of the jaw stretch reflex response as revealed by both sEMG and imEMG. This effect appears to be independent of the level of excitation of the muscle and not related to volume effects of the injected saline. A change in the sensitivity of the fusimotor system during muscle pain is suggested as an explanation.

The relationship between nocturnal jaw-muscle activity and temporomandibular disorders (TMD) is still controversial. The aim of this study was to investigate the effect of selective slow wave sleep (SWS = non-rapid-eye-movement (NREM) stage 3 + 4) deprivation on jaw-muscle activity using a new automatic system. Ten healthy men without signs of symptoms of TMD participated. The subjects slept in the laboratory for six continuous nights including one adjustment night, one baseline night, three nights with experimental sleep deprivation and one recovery night. Polysomnographic recordings of electroencephalography (EEG) and electromyography (EMG) were obtained for recognition of sleep stages and masseter muscle activity. During the three experimental nights, computer-controlled sound stimulation (60--90 dB(A), 1000 Hz) were given as long as the subjects were in SWS. Maximum voluntary occlusal force (MVOF), pain pressure threshold (PPT) and visual analogue scales (VAS) were used to assess the state of the masseter muscles every morning and evening during the study period. The results showed that the time spent in SWS was significantly decreased during the first sleep deprivation night, but there were no significant effects on nocturnal EMG activity (i.e. the numbers of bruxism episodes per hour of sleep, bruxism bursts per episodes bruxism bursts per hour of sleep), MVOF, VAS or PPT. Furthermore, the automatic system only deprived the SWS in five subjects for the following two nights although the sound stimulation was given at the maximum intensity. These results suggest that deprivation of SWS may not interact immediately with nocturnal jaw-muscle activity and jaw-muscle pain.

Electromyographic activity was recorded in the masseter muscle to investigate whether the firing characteristics of single motor units (SMUs) were affected by muscle pain. Capsaicin was injected into the masseter to induce pain. The interspike interval (ISI) and recruitment threshold of SMUs were measured while subjects performed isometric contractions at 5, 7.5, 10, 15, and 20% of maximum voluntary contraction. All subjects were able to maintain a stable isometric force during pain, but the mean ISI was significantly increased without changing the recruitment threshold. In all the experimental conditions, the firing frequency increased with increasing force, and SMUs recruited at low force fired at higher rates for all force levels. These results suggest that acute stimulation of nociceptive muscle afferents inhibits SMU activity without changing recruitment order in the homonymous muscle., (Copyright 2000 John Wiley & Sons, Inc.)

Aims: Strong jaw muscle exercises such as tooth grinding in sleep bruxism are frequently believed to be a predisposing factor in myogenous types of temporomandibular disorders. However, it is not known whether tooth grinding in sleep bruxism is associated with increased sensitivity to intramuscular stimuli. This study therefore compared the hyperalgesic effects of an intramuscular injection of capsaicin into the right masseter with and without a prior experimental tooth-grinding exercise., Methods: Ten healthy men participated in 2 randomized sessions (exercise, non-exercise session) separated by 1 week. In the exercise session, 0.1 mL capsaicin (100 micrograms/mL) was injected into the right masseter immediately after 45 minutes of experimental tooth grinding. In the non-exercise session, the exact same paradigm was used, except that the experimental tooth grinding was omitted. The perceived intensity of pain evoked by intramuscular capsaicin was scored on a 100-mm visual analog scale (VAS). Pain detection thresholds (PDTs) to pressure stimuli and maximal voluntary occlusal force (MVOF) were measured before capsaicin injection; 5, 15, and 45 minutes after the injection; and once a day for the following 3 days., Results: Injections of capsaicin into an exercised or non-exercised masseter did not cause significant differences in peak pain intensity on the VAS (57 +/- 6 mm in exercised masseter vs. 53 +/- 6 mm in non-exercised masseter; P = 0.464). The PDTs in the exercised masseter were significantly decreased for up to 1 day after the capsaicin injection (P < or = 0.038), whereas PDTs in the non-exercised masseter were decreased for only 5 minutes (P = 0.017). The MVOF on the right side was decreased 5 minutes after the capsaicin injection in both sessions (P < 0.010). The MVOF on the left side was significantly reduced for up to 15 minutes after the capsaicin injection in the exercise session only (P < 0.019)., Conclusion: Increased sensitivity to percutaneous pressure stimuli probably reflects a post-exercise muscle soreness following tooth grinding, whereas intramuscular sensitivity to noxious chemical stimuli immediately following exercise seems to be unchanged.

Convergence of various afferent inputs onto brain-stem neurons may play an important role in the regulation of trigeminal motor function. The present study examined the efficacy of nociceptive and non-nociceptive perioral stimulation for the modulation of the two exteroceptive suppression periods (ES1 and ES2) in human jaw-closing muscles. The inhibitory jaw-reflexes, ES1 (10-15 ms onset) and ES2 (40-50 ms onset), were recorded as the surface electromyogram of masseter and temporalis muscles in 14 healthy subjects. Non-painful electrical stimuli were applied to the right mental nerve while the subject was biting at 50% of the maximal voluntary force. Five conditions were compared: baseline, repetitive tactile stimulation (1 Hz) on the right cheek, topical application of capsaicin (5%) on the right cheek, repetitive tactile stimulation plus capsaicin, and postbaseline. The perceived intensity of the electrical stimuli was evaluated by the subjects on a 0-10 rating scale. Capsaicin alone failed to induce significant changes of ES1 and ES2; tactile stimulation alone induced a significant delay in the onset of ES2 (P < 0.001). During repetitive tactile stimulation plus capsaicin, the duration of ES1 and ES2 was shortened (ES1 and ES2: P < 0.001) and the degree of suppression was reduced (ES1: P < 0.05; ES2: P < 0.005). Perceived intensity of the electrical stimuli was unchanged during the different experimental conditions. The present results suggest that summation of simultaneous nociceptive and non-nociceptive inputs plays an important role in the modulation of the neural pathways involved in the short-latency ES1 and long-latency ES2.

The interaction between muscle pain and motor function of the jaw has been examined in recent years, but the nature of the modulation of the short-latency stretch reflex by pain is not fully understood. In this study, the reflex responses to stretch were measured in single low-threshold motor units that were kept discharging at a constant frequency, before, during and after the induction of experimental pain in one masseter muscle by controlled infusion of hypertonic saline. The probability of evoking a reflex response in individual motor units in the painful muscle at near-monosynaptic latency was reduced by a mean of about 20%. However, the overall reflex response in the surface electromyogram of both the ipsi- and contralateral masseter muscles was greater during pain. This was apparently a secondary response to the pain-induced increase in pre-stimulus activity in the motoneurone pools of both muscles, because increased motoneurone excitability may facilitate stretch reflexes. It is concluded that the most likely explanation for the reduced reflex response of low-threshold masseter motor units during experimental pain is a tonic reduction in the fusimotor drive to the masseter spindles.

The bite force at different levels and the corresponding electromyographic (EMG) activity of the masseter and anterior temporalis muscles were recorded in 12 healthy subjects in order to evaluate the modulation of EMG-force curves by a standardized painful stimulus. Hypertonic saline (5%) was infused into the right masseter muscle for up to 15 min to induce pain. The pain intensity was scored continuously by the subjects on a 10-cm visual analogue scale (VAS). Subjects were asked to bite on a force transducer at the maximum voluntary bite force (MVBF). They were then asked to bite at submaximum levels of 12, 25, 37, 50, 67, 75 and 87% of MVBF. The biting was performed in three different positions (right first molar, left first molar and incisor) before, during and after infusion. Hypertonic saline caused moderate pain during infusion (mean VAS +/- s.e.m. = 6.5+/-0.5 cm). Both the MVBF and the maximum EMG activity in the right masseter and the left anterior temporalis muscles were significantly decreased during muscle pain when the subjects bit on the painful side. The EMG-force curves could be fit by linear relationships. The slope of the curve became less steep in the right masseter muscle during and after painful biting in every position. The results suggest that tonic saline-induced jaw-muscle pain is able to modulate the motor unit recruitment pattern of the jaw-closing muscles on the painful side. The main effect of pain in this experiment was an inhibition of static EMG activity.

Inhibitory reflex responses to electrical stimulation of the mental nerve were studied in recordings from single motor units (SMU) in the human masseter muscle. A new analytical technique for spike train data was used. Electrical stimuli were delivered to the mental nerve when the SMU fired with two consecutive inter-spike intervals (ISIs) within the range of 90 ms to 110 ms. Stimuli were delivered with increasing stimulus delays after the preceding SMU action potential (AP). Sham, non-painful, and painful stimulus intensities were applied. The post-stimulus firing probability of the SMU was progressively decreased among the three conditions. Analysis of the relation between stimulus delays and ISI for the first post-stimulus APs revealed a linear relation which was shifted upward, and the slope was increased with increasing stimulus intensity. This may be explained by a differential effect of the increasing stimulus intensity on the duration and amplitude of the inhibitory post-synaptic potential. The methods used in the present study provide a useful means of quantifying the effects of motoneuron excitability in detail., (Copyright 2000 John Wiley & Sons, Inc.)

Perioral electrical stimuli cause inhibitory reflex responses in single motor-units (SMU) and surface electromyographic (EMG) recordings from voluntary contracted human jaw-closing muscles. Tonic experimental masseter pain has recently been shown to reduce the inhibitory reflex response in surface EMG recordings but the effect on SMU activity has not been described. In this study, motor-unit action potentials were recorded with wire electrodes inserted into the left masseter in eleven subjects. The subjects kept the SMU firing rate around 10 Hz by feedback. Ninety-nine electrical stimuli were applied sequentially to the left mental nerve with increasing stimulus delays in steps of 1 ms after the preceding motor unit action potential. The inhibitory reflex in SMU was recorded before, during and after infusion of hypertonic saline (5%) into the ipsilateral masseter muscle. Spike train data were used to calculate (1) the mean pre- and post-stimulus inter-spike-intervals (ISI) in all of the 99 trials, (2) cumulative changes in firing probability, and (3) estimation of the compound inhibitory post-synaptic potential (IPSP) in the masseter motoneuron. Tonic masseter pain did not change pre-stimulus SMU firing characteristics but the mean ISI for the first post-stimulus discharge (158.2+/-9.2 ms) was significantly decreased compared to the pre-pain (175.8+/-11.3 ms, P<0.05) and post-pain conditions (172. 6+/-11.6 ms, P<0.05). The post-stimulus firing probability was significantly increased and the relative amplitude of the estimated IPSP significantly decreased during tonic masseter pain compared to pre-pain and post-pain conditions. In conclusion, this study indicates that tonic masseter pain has a net excitatory effect on the inhibitory jaw-reflexes, which could be mediated by presynaptic mechanisms on the involved motoneurons.

The exteroceptive suppression periods (ES) in human jaw-closing muscles can be conditioned by a wide range of somatosensory stimuli and cognitive states. The aim of this study was to examine the effects of tonic experimental jaw-muscle pain versus remote muscle pain on the short-latency (ES1) and long-latency (ES2) reflex in the jaw-closing muscles. Twelve healthy subjects participated in the first experiment with jaw-muscle pain. In random order 5% hypertonic or 0.9% isotonic saline was infused into the left masseter muscle for 15 min. The pain intensity was scored continuously by the subjects on a 10-cm visual analogue scale (VAS). Electromyographic (EMG) activity was recorded bilaterally from the masseter and temporalis muscles during the pre-infusion, early phase of infusion (from 120 to 480 s), late phase of infusion (from 540 to 900 s) and post-infusion. An electrical stimulus was delivered to the skin above the left mental nerve (ipsilateral to the painful muscle) to evoke the ES in the contracting jaw-closing muscles. Ten healthy subjects participated in experiment 2 which was as identical to experiment 1 except that the electrical stimulus was delivered to the right mental nerve (contralateral to the painful muscle). Nine healthy subjects participated experiment 3 where remote muscle pain was induced in the left tibialis anterior muscle. In experiment 1 painful infusion of hypertonic saline caused a significantly later onset latency of ES2 in the left masseter muscle during the late phase of infusion compared to pre-infusion values (P < 0.05). The duration of ES2 in the same muscle was significantly shorter during the late infusion phase compared to pre- and post-infusion values (P < 0.05) and the degree of suppression was significantly reduced during the early infusion compared to the pre-infusion values (P < 0.05). Isotonic saline did not influence the ES1 or ES2. In experiment 2, similar significant inhibitory changes were found in the ES2 on the painful side. In experiment 3, no significant effects on ES1 and ES2 were observed during painful infusion of hypertonic saline into the leg muscle. These results indicate that the effects of tonic jaw-muscle pain on ES2 can be distinguished from a generalized effect of muscle pain. Furthermore, there seems to be a differential and lateralized effect of jaw-muscle pain on the brain stem reflex circuits involved in the generation of ES1 and ES2 probably through a presynaptic mechanism.

Objectives: Two periods of exteroceptive suppression are elicited in human masseter muscle following perioral electrical stimulation: ES 1 and ES2. Furthermore, in the masseter EMG, two periods of apparent excitation can be distinguished from the background activity: intersuppression period (ISP) and post-suppression period (PSP). In the present study, the relationship between nociception and ES1, ISP and PSP was investigated., Methods: The reflex responses were electrically elicited in 15 volunteers. A novel computer algorithm was used to detect and quantitate ES1, ES2, ISP and PSP., Results: (a) ES1 and ES2 were more susceptible to changes in magnitude of suppression and excitation, respectively, than ISP and PSP; (b) the on-set latencies were almost unaffected; (c) both ES1 and ES2 occurred at stimulus intensities well below pain threshold; (d) magnitude of ES1 and ES2 suppression increased with increasing stimulus intensity, but supra pain threshold stimulation did not result in further suppression; and (e) no correlation was found between perceived stimulus intensity and ES1, ISP or PSP., Conclusions: The increase in ES1 and ES2 suppression seen in our study at increasing stimulus intensity is suggested to be mediated by activity in both nociceptive and non-nociceptive fibres converging onto central interneurones in the reflex circuits. We suggest that neither ISP nor PSP are reflex responses. It is unlikely that ES1, ES2, ISP and PSP evoked by electrical stimuli are directly linked to noxious activity.

Aims: Pain in some bruxers has been suggested to represent a state of postexercise muscle soreness. This study examined the effect of voluntary, controlled grinding movements on the development of pain and soreness in the masticatory system., Methods: Twelve healthy men (21 to 42 years old) without signs or symptoms of temporomandibular disorders (TMD) participated. Nine trials of 5 minutes of repeated grinding from the intercuspal position to the right canine-canine position (0.5 Hz) were performed on the first day. During the lateral excursions, the electromyographic (EMG) activity of the right masseter muscle was kept above 50% of maximal voluntary occlusal force (MVOF) with the use of visual feedback. The subjects rated pain intensity, unpleasantness, and soreness on 100-mm visual analogue scales (VAS); other pain measures, including the McGill Pain Questionnaire, were also used. Before and after the exercise trials, the MVOF was determined, and pain detection thresholds (PDT) to pressure stimuli were measured at 9 different sites on the masseter muscles. The subjects returned to the laboratory the 3 following days, where VAS, PDT, and MVOF were measured., Results: Immediately following the last grinding trial, there was a significant increase in VAS and MPQ scores of pain intensity, unpleasantness, and soreness, as compared to baseline values (analysis of variance, P < 0.001). There was still a significant effect from grinding on the VAS score of muscle soreness on the following days, with a peak the first day after the exercise (Tukey test, P < 0.023). Pain was frequently (in 7 of 12 subjects) reported in or around the temporomandibular joint. There was a significant effect from grinding on PDT at both masseter muscles (analysis of variance, P < 0.043), with significantly lower PDT the first day after the grinding exercise (Tukey test, P < 0.046). There were no effects from grinding on MVOF., Conclusion: These findings suggest that significant but low levels of postexercise muscle soreness can be elicited by standardized grinding movements in the masticatory system of healthy subjects.

During contraction of the jaw-closing muscles, afferent input from the intraoral and perioral region can elicit two bilateral suppression periods (SP1 and SP2, respectively) in the masseter electromyogram (EMG). Non-painful electrical stimulation 2 cm from the left labial commissure was used in the present study to evoke these trigeminal inhibitory reflexes. The subjects maintained a level of 50% of their maximum masseter EMG. The degree of suppression was quantified as the percentage suppression of the mean EMG activity in a fixed post-stimulus interval (SP2, 40-90 ms). Further, brief (200 ms) painful radiant heat conditioning stimuli were delivered to the ipsilateral cheek, in order to investigate the influence of nociceptive input on the (non-nociceptive) trigeminal masseter inhibitory reflex. Nine different conditions combining radiant heat and electrical stimuli were used. Twelve stimuli were presented for each condition. The radiant heat preceded the electrical test stimuli by fixed inter-stimulus intervals (ISI), ranging from 100 ms to 500 ms. At 250-350 ms ISIs, the bilateral SP2 suppression was significantly reduced to less than 10%, in comparison to an average suppression degree of 32.5% without conditioning stimuli. The subjects perceived the heat stimulus before the electrical stimulus for a majority of the 12 pairs of stimuli at these ISIs. No differences were found in the VAS ratings for the different conditions. For the contralateral SP1, larger suppression was seen for the 300 ms ISI compared with stimulation without conditioning heat stimuli. Onset and offset for the SP1 was, however, only detected in three subjects using a criteria of 20% suppression of the pre-stimulus activity. A pre-pulse inhibitory effect onto inter-neurons in the SP2 pathways or habituation of the same inter-neurons by the heat stimuli are suggested as possible explanations for the interaction between the non-nociceptive and nociceptive input in the present study.

The mutual links between muscle pain and resting electromyographic (EMG) activity are still controversial. This study described effects of experimental muscle pain on resting EMG activity in a jaw-closing muscle and a leg muscle. Pain was induced by injections of hypertonic saline into the muscles in 10 subjects. Injections of isotonic saline served as a control. The pain intensity was scored on visual analog scales (VAS) and surface and intramuscular wire EMGs were obtained from the resting muscles before, during, and after saline injections. EMG activity was analyzed in 30-s intervals and demonstrated, in both muscles, significant increases 30-60 s after injection of hypertonic saline, but not after injection of isotonic saline. In contrast to the transient increase in EMG activity, the pain sensation lasted up to 600 s after injection of hypertonic saline. It was concluded that acute muscle pain is unable to maintain longer-lasting resting muscle hyperactivity.