Kelun Wang

Injection of nerve growth factor into human masseter muscle evokes long-lasting mechanical allodynia and hyperalgesia

&NA; 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 (1 h, 1, 7, 14, 21 and 28 days) of NGF (5 &mgr;g 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 8 h 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.

Glutamate-evoked pain and mechanical allodynia in the human masseter muscle

&NA; 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, 1.0 M 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 1.0 M 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 1.0 M may reflect allodynia to mechanical stimuli. This process of sensitization was not gender‐dependent. The present results suggest that injection of 1.0 M 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 effects of intra-oral pain on motor cortex neuroplasticity associated with short-term novel tongue-protrusion training in humans

Abstract To determine if short‐term (15 min) training in a novel tongue‐task is associated with rapid neuroplasticity of the tongue primary motor area (MI) in the human cerebral cortex, and if intra‐oral tonic pain affects the tongue MI neuroplasticity and tongue‐task training performance. Nine healthy volunteers (7 men, 2 women, mean age 24 ± 1.1 years) participated in two cross‐over training sessions in which the application to the tongue of the algesic chemical capsaicin (1%) or vehicle cream was randomized. Prior to and again immediately after 15 min of training in a tongue‐protrusion task, transcranial magnetic stimulation (TMS) was applied to the MI in each session and motor evoked potentials (MEPs) were recorded in the tongue musculature and the first dorsal interosseous (FDI) muscle (as control). Neuroplasticity of the tongue MI, as reflected in a significantly enhanced TMS–MEP stimulus–response curve and reduced MEP threshold, was observed after the vehicle session but not after the capsaicin session. Subjects’ overall mean performance scores were significantly higher in the vehicle session than in the capsaicin session. MI neuroplasticity may rapidly occur in association with successful performance in novel tongue‐task training, but intra‐oral tonic pain interferes with these effects. These findings suggest that nociceptive input modulates MI neuroplasticity associated with novel motor training and may impair the ability to learn a new motor task.

Associations between pain and neuromuscular activity in the human jaw and neck muscles.

&NA; The aim of this study was to test the effects of glutamate‐evoked jaw or neck muscle pain on electromyographic (EMG) activity of jaw and neck muscles in humans. EMG recordings were made from left (MAL) and right (MAR) masseter muscles, and right sternocleidomastoid (SCM) and splenius (SP) muscles in three different head positions (head rest, head back, head right) or during maximal jaw clenching in 19 men. Glutamate (1 M) or isotonic saline was injected into MAR or SP, and induced pain was recorded on visual analogue scales. EMG activity in MAL and MAR was increased in the head back position compared to head rest and head right positions, whereas EMG activity in SCM and SP was progressively increased as the head was moved from rest position to head back to head right positions. Glutamate‐evoked MAR pain was associated with increases in EMG activity in MAR, SCM and SP at rest but not in the head back or head right positions. Glutamate‐evoked SP pain was associated with an increase in SP EMG activity at rest and a decrease in SCM EMG activity in the head right position. Decreases in jaw clench‐related EMG activity were observed in MAL, MAR and SCM muscles only during glutamate‐evoked MAR pain. Isotonic saline injections induced no pain or EMG changes. In conclusion, experimental neck pain is not associated with tonic increases in jaw EMG activity although jaw muscle pain can be linked to increases in neck EMG activity with the head and jaw at rest.

Modulation of exteroceptive suppression periods in human jaw-closing muscles by local and remote experimental muscle pain.

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.

Effects of subcutaneous administration of glutamate on pain, sensitization and vasomotor responses in healthy men and women

Abstract The present study aimed to investigate if (1) subcutaneous injection of glutamate induces pain, sensitization and vasomotor responses in humans and (2) if sex differences exist in these responses. Thirty healthy volunteers (men‐15 and women‐15) were included. Each subject received four subcutaneous injections (0.1 ml; glutamate 100, 10, 1 mM and isotonic saline 0.9%) into the forehead skin in two sessions separated by one week. Assessments of pain intensity (VAS), quality, distribution; area of pinprick hyperalgesia; pressure pain threshold (PPT) at the injection site; surface skin temperature and local blood flow were performed at predetermined time points. The highest concentration of glutamate evoked the highest pain intensity, the longest duration of pain and the largest pain area under the VAS–time curve (P < 0.001) in both men and women, although responses in women were larger than in men (P < 0.05). The face‐chart pain area was the largest for the highest concentration of glutamate (P < 0.001) and women drew a larger pain area than men (P = 0.024). The area of pinprick hyperalgesia was the largest for glutamate 100 mM (P < 0.001) and women indicated a larger area than men (P < 0.001). Concentration‐dependent local vasomotor responses were found following the subcutaneous injection of glutamate but there was no sex difference in this effect. Glutamate 100 mM significantly reduced the PPT values (P < 0.001) without sex‐related differences. The present study demonstrates for the first time that subcutaneous injection of glutamate evokes pain, vasomotor responses and pinprick hyperalgesia in human volunteers and that there are sex‐related differences in some of these responses.

Effect of tonic muscle pain on short-latency jaw-stretch reflexes in humans

&NA; The modulation of human jaw‐stretch reflexes by experimental muscle pain was studied in three experiments. Short‐latency reflex responses were evoked in the masseter and temporalis muscles by fast stretches (1 mm displacement, 10 ms ramp time) before, during and 15 min after a period with tonic pain. In Expt. I, a dose of 5.8% hypertonic or 0.9% 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 was kept constant at 15% of maximal effort by visual feedback and on‐line calculation of the root‐mean‐square value of the surface electromyogram (sEMG). In Expt. II, a dose of 5.8% saline was infused into the left masseter but with feedback from the right masseter sEMG (n=12). In Expt. III, both sEMG and intramuscular (im) EMG was recorded from the left and right masseter muscles. The feedback was from either the sEMG or imEMG of the left masseter in which 5.8% saline was infused (n=12). In all experiments, subjects continuously rated their perceived pain intensity on a 10‐cm visual analogue scale (VAS). Infusion of 5.8% saline caused moderate levels of pain (mean VAS 4.9–5.0 cm) whereas infusion of 0.9% saline was almost pain‐free (mean VAS 0.3 cm). The pre‐stimulus EMG activity in the masseter, which served as the feedback muscle during the recording, was constant across the different conditions. During painful infusion of 5.8% saline in Expts. I and III, the pre‐stimulus sEMG activity in the non‐painful masseter was significantly higher than baseline when the sEMG on the painful side was used as feedback signal, and in Expt. II significantly lower on the painful side when the non‐painful side served as feedback signal (Student–Newman–Keuls: P<0.05). Isotonic saline did not affect the pre‐stimulus sEMG activity or the jaw‐stretch reflex parameters. The peak‐to‐peak amplitude of the stretch reflex in the painful masseter normalized to the pre‐stimulus EMG activity was significantly higher during the pain conditions compared with the pre‐ and post‐infusion conditions in all experiments. These results indicate that experimental jaw‐muscle pain facilitates the short‐latency (8–9 ms), probably monosynaptic, jaw‐stretch reflex as revealed by both sEMG and imEMG. This effect could not be accounted for by variability in pre‐stimulus EMG activity. An increased sensitivity of the fusimotor system at this level of static muscle excitation is suggested as a possible mechanism, which could contribute to an increased stiffness of the jaw‐muscles during pain.

Capsaicin-induced Muscle Pain Alters the Excitability of the Human Jaw-stretch Reflex

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 μg) 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.

Glutamate evoked neck and jaw muscle pain facilitate the human jaw stretch reflex

OBJECTIVE Although pain and neuromuscular function are clearly linked in several clinical conditions manifested in the craniofacial and cervical regions, it is unclear if pain in these regions influences reflexly evoked activity in the jaw or neck muscles in humans. The aim of the present study was to test the effects of glutamate-evoked jaw or neck muscle pain on the jaw stretch reflex recorded in both jaw and neck muscles. METHODS Nineteen healthy men participated in the study. Electromyographic (EMG) recordings were made from the left masseter (MAL) and right masseter (MAR) muscles and the right sternocleidomastoid (SCM) and splenius (SP) muscles. Glutamate (1 M) or isotonic saline was injected into the MAR or right SP in random order and then the other solution was injected 1-3 weeks later. Pain intensity was scored on a 10 cm visual analogue scale. Stretch reflexes were evoked by standardized jaw stretches before, during and 15 min after the end of the experimental muscle pain. Twenty trials were averaged in each condition. RESULTS Pain evoked by MAR or SP glutamate injections was associated with a significant increase in the stretch reflex amplitude recorded in both MAR and SCM. The onset and offset times and duration of the stretch reflex did not change in any muscle during the various pain conditions. Injection of isotonic saline into the MAR or SP did not produce any significant change in the reflex parameters in any of the muscles. CONCLUSIONS The results indicate the close interplay between the craniofacial and cervical regions in the neuromuscular changes that may result from musculoskeletal pain in either region. SIGNIFICANCE The changes in neuromuscular activity documented in this study may be involved in the clinical occurrence of altered muscle activity in the orofacial and cervical regions as a result of deep tissue trauma and pain.

Effect of muscle relaxants on experimental jaw-muscle pain and jaw-stretch reflexes: a double-blind and placebo-controlled trial.

A randomised, double‐blind, placebo‐controlled three‐way cross‐over study was performed to investigate the effect of two muscle relaxants (tolperisone hydrochloride and pridinol mesilate) on experimental jaw‐muscle pain and jaw‐stretch reflexes. Fifteen healthy men participated in three randomised sessions separated by at least 1 week. In each session 300 mg tolperisone, 8 mg pridinol mesilate or placebo was administered orally as a single dose. One hour after drug administration 0.3 ml hypertonic saline (5.8%) was injected into the right masseter to produce muscle pain. Subjects continuously rated their perceived pain intensity on an electronic 10‐cm visual analogue scale (VAS). The pressure pain threshold (PPT) was measured and short‐latency reflex responses were evoked in the pre‐contracted (15% maximal voluntary contraction) masseter and temporalis muscles by a standardised stretch device (1 mm displacement, 10 ms ramp time) before (baseline), 1 h after medication (post‐drug), during ongoing experimental muscle pain (pain‐post‐drug), and 15 min after pain had vanished (post‐pain). Analysis of variance demonstrated significantly lower VAS peak pain scores (5.9±0.4 cm) after administration of tolperisone hydrochloride compared with pridinol mesilate (6.8±0.4 cm) and placebo (6.6±0.4 cm) (P=0.020). Administration of pridinol mesilate was associated with a significant decrease in PPTs compared with tolperisone hydrochloride and placebo (P=0.002) after medication, but not after experimental jaw‐muscle pain. The normalised peak‐to‐peak amplitude of the stretch reflexes were not significantly influenced by the test medication (P=0.762), but were in all sessions significantly facilitated during ongoing experimental jaw‐muscle pain (P=0.034). In conclusion, tolperisone hydrochloride provides a small, albeit significant reduction in the perceived intensity of experimental jaw‐muscle pain whereas the present dose had no effect on the short‐latency jaw‐stretch reflex.