Interactions of glutamate and capsaicin-evoked muscle pain on jaw motor functions of men

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Abstract

Objective

The aim of the study was to investigate the interaction between glutamate and capsaicin-evoked muscle pain on human jaw motor functions.

Methods

Fifteen male volunteers participated. Glutamate or capsaicin or isotonic saline, in a paired-sequence order, was injected randomly into the right or left masseter muscle. Two injections were given in a double-blinded design 25Ā min apart in one session/week over four weeks: isotonic saline (A1) followed by glutamate (A2), capsaicin (B1) followed by glutamate (B2), isotonic saline (C1) followed by capsaicin (C2), and glutamate (D1) followed by capsaicin (D2). The resting electromyographic (EMG) activity of the right and left masseter muscles, maximum voluntary bite force (MVBF), and maximum voluntary jaw opening (MVJO) were recorded before and after injection and subsequently at 5-min intervals for 50Ā min. The pain intensity was recorded on a 0ā€“10 numerical rating scale during each MVBF or MVJO jaw function.

Results

Resting EMG activity was significantly increased after 5Ā min of D2 (ANOVA: PĀ =Ā 0.028) injection. The percentage change (compared with baseline) in EMG activity was significantly different between D2 (116.1Ā Ā±Ā 6.1%) and C2 (102.1Ā Ā±Ā 3.4%) injections (paired t-test: PĀ =Ā 0.039). The MVBF and MVJO were significantly decreased after injection of glutamate or capsaicin, however, there was no significant difference in the relative decrease between A2 and B2, or between C2 and D2 at any time point (PĀ >Ā 0.152). There was a significantly higher peak pain rating after D2 compared to C2 during MVBF or MVJO (PĀ <Ā 0.022), whereas no significant difference in peak pain ratings was found between A2 and B2 (PĀ >Ā 0.084). There were significant negative correlations between pain ratings and MVBF or MVJO (Pearson correlation: PĀ <Ā 0.001).

Conclusions

The results indicate that intramuscular administration of glutamate and capsaicin induces muscle pain which has the potential to perturb some normal jaw motor functions.

Significance

The present findings suggest that peripheral glutamate and capsaicin receptor mechanisms interact to affect some jaw motor as well as sensory (i.e. pain) functions and provide new insights into the complexity of orofacial pain. Management approaches that target the peripheral nervous system and receptor mechanisms may prevent such changes in jaw motor function.

Introduction

Glutamate is the endogenous agonist for excitatory amino acid (EAA) receptors (Collingridge and Lester, 1989, Monaghan et al., 1989, Cairns et al., 1998, Cairns et al., 2002, Cairns et al., 2003a). Although glutamate is a well-documented central excitatory neurotransmitter, a number of recent studies have provided data indicating a role for peripheral EAA receptors in the transduction of nociceptive information (see Carlton, 2001, Carlton et al., 2003, Lam et al., 2005a, Lam et al., 2005b, Lam et al., 2008, Lam et al., 2009a, Lam et al., 2009b, Cairns et al., 1998, Cairns et al., 2002, Cairns et al., 2003a, Cairns et al., 2006, Dong et al., 2006, Dong et al., 2007). Glutamate is present in both the central and peripheral terminals of trigeminal and dorsal root ganglion neurons and noxious stimulation of primary afferent fibers results in the release of glutamate from the peripheral as well as central terminals of trigeminal and spinal afferent fibers (Salt and Hill, 1983, Azerad et al., 1992, Westlund et al., 1992, Bereiter and Benetti, 1996, Keast and Stephensen, 2000, Lam et al., 2005b). In addition, glutamate injection into the rat masseter muscle or temporomandibular joint (TMJ) reflexly evokes a dose-dependent increase in jaw muscle electromyographic (EMG) activity (Cairns et al., 1998, Cairns et al., 2001a, Cairns et al., 2001b, Cairns et al., 2002, Lam et al., 2004, Lam et al., 2005a, Lam et al., 2005b) and central sensitization of trigeminal brainstem nociceptive neurons (Lam et al., 2008, Lam et al., 2009b). Similarly, glutamate injection into the human masseter muscle causes pain and mechanical hyperalgesia that may be attenuated by co-injection of a NMDA receptor antagonist (Cairns et al., 2001a, Cairns et al., 2003a, Cairns et al., 2003b, Svensson et al., 2003, Svensson et al., 2005, Castrillon et al., 2008). Our previous studies have also indicated that changes in jaw muscle activity may accompany the glutamate-induced pain since pain evoked by masseter or splenius glutamate injection is associated with a significant increase in the stretch reflex amplitude and resting EMG activity in the masseter or sternocleidomastoid muscles (Cairns et al., 2003b, Wang et al., 2004, Svensson et al., 2004, Svensson et al., 2005). We have also shown that the masseter exteroceptive suppression response was significantly decreased and masseter resting EMG activities significantly increased after glutamate injection into the masseter (Torisu et al., 2006, Torisu et al., 2007), suggesting effects of glutamate-induced muscle pain on jaw motor functions.

The vanilloid type 1 receptor (TRPV1) is another peripheral receptor which can be activated by the irritant capsaicin, protons or noxious heat and can result in the neurogenic release of EAAs (Caterina et al., 1997, Tominaga et al., 1998, deGroot et al., 2000, Benham et al., 2003, Jordt et al., 2003, Gold, 2005, Palazzo et al., 2008, Ro et al., 2009). Capsaicin applied to skin, muscle, and other tissues such as the TMJ has been shown to produce inflammation, activate and sensitize trigeminal and spinal small-diameter nociceptive afferents as well as dorsal horn neurons, and also to evoke nociceptive behavior in animals and intense pain, hyperalgesia and referred pain in humans (Simone et al., 1991, Simone et al., 1997, Marchettini et al., 1996, Ko et al., 2000, Arima et al., 2000, Witting et al., 2000a, Witting et al., 2000b, Hu et al., 2005, Lam et al., 2005a, Lam et al., 2005b, Lam et al., 2008, Lam et al., 2009a, Lam et al., 2009b, Gazerani et al., 2005, Gazerani et al., 2007). Also, we have previously shown that injection of capsaicin into human jaw muscle causes a significant decrease in maximal voluntary biting force (Arima et al., 2000) and a significant facilitation of the jaw stretch reflex (Wang et al., 2002). In addition, we have previously documented interactions between glutamate and capsaicin injections in inducing pain and sensitization in human jaw muscles (Arendt-Nielsen et al., 2008).

Despite these findings of peripheral EAA and TRPV1 processes, little attention has been given to the possible interactive influences on motor activity of glutamate and capsaicin injections. Recent animal studies have revealed that peripheral application of glutamate or capsaicin may activate or induce peripheral sensitization in a subpopulation of trigeminal nociceptive afferents innervating deep craniofacial tissues. Injection of glutamate into the rat TMJ sensitizes nociceptive afferent responses to capsaicin injection into the TMJ whereas capsaicin desensitizes responses to glutamate (Lam et al., 2009a). Capsaicin injection into the rat TMJ evokes significant increases in EMG activity in both digastric and masseter muscles whereas pre-injection of EAA receptor antagonist into the TMJ results in a significant concentration-related reduction in the capsaicin-evoked EMG activity (Tang et al., 2004, Lam et al., 2005a, Lam et al., 2005b). Thus, the aim of this study was to investigate human jaw motor functions during muscle pain induced by injection of glutamate or capsaicin, and the interactions between glutamate and capsaicin in affecting these motor functions.

Section snippets

Subjects

Fifteen healthy male volunteers (mean ageĀ Ā±Ā SD: 27Ā Ā±Ā 5Ā years) participated in a double-blind, crossover experiment. The subjects had no signs or symptoms of temporomandibular disorders (TMD) (Dworkin and LeResche, 1992) and were recruited from university students. The study protocol was approved by the local ethics committee in Denmark (County of Aarhus: 20040074) and followed the guidelines set out by the Helsinki Declaration. Informed consent was obtained from all subjects.

Experimental protocol

Glutamate (0.2Ā ml, 1Ā M) or

Resting EMG changes

The baseline measurements of the resting EMG activity on the injected side were 1.77Ā Ā±Ā 0.09Ā Ī¼V in the A, 1.86Ā Ā±Ā 0.13Ā Ī¼V in the B, 1.70Ā Ā±Ā 0.09Ā Ī¼V in the C, and 1.69Ā Ā±Ā 0.10Ā Ī¼V in the D conditions. There were no significant differences between the four conditions for the baseline EMG values (ANOVA: PĀ =Ā 0.277).

Resting EMG activity on the injected side was significantly increased at 5Ā min only after the D2 injection (PĀ =Ā 0.028) (Fig. 2D). The relative change in EMG activity was significantly higher at 5Ā min after D2

Discussion

The present study has demonstrated that injection of either glutamate or capsaicin into the masseter muscle induced muscle pain and that some jaw motor functions were attenuated by glutamate or capsaicin-evoked muscle pain. A significant negative correlation was found between pain ratings and the jaw motor functions. The pain ratings during MVBF and MVJO were also significantly higher after glutamateā€“capsaicin injection compared to isotonic salineā€“capsaicin injection. The findings suggest that

Acknowledgment

This study was supported by US National Institutes of Health Grant R01DE015420.

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