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Evidence That Excitatory Amino Acid Receptors Within the Temporomandibular Joint Region Are Involved in the Reflex Activation of the Jaw Muscles

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Evidence That Excitatory Amino Acid Receptors Within the Temporomandibular Joint Region Are Involved in the Reflex Activation of the Jaw Muscles The Journal of Neuroscience, October 1, 1998, 18(19):8056–8064 Evidence That Excitatory Amino Acid Receptors within the Temporomandibular Joint Region Are Involved in the Reflex Activation of the Jaw Muscles Brian E. Cairns, Barry J. Sessle, and James W. Hu Department of Oral Physiology, Faculty of Dentistry, The University of Toronto, Toronto, Ontario M5G 1G6, Canada We have previously shown that injection of the inflammatory comparable magnitude. Co-application of the NMDA receptor irritant and small-fiber excitant mustard oil (MO) into the tem- antagonist DL-2-amino-5-phosphonovalerate (0.5 mmol) signif- poromandibular joint (TMJ) region can reflexively induce a pro- icantly reduced the magnitude of the glutamate- and NMDA- longed increase in the activity of both digastric and masseter evoked ipsilateral jaw muscle responses without affecting re- muscles in rats. It is possible that peripheral excitatory amino sponses evoked by AMPA. In contrast, co-application of the acid (EAA) receptors play a role in this effect, because MO- non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline- evoked increases in jaw muscle activity are attenuated by 2,3-dione (1 nmol) significantly reduced the magnitude of the preapplication of the noncompetitive NMDA receptor antago- glutamate- and AMPA-evoked ipsilateral jaw muscle responses nist MK-801 into the TMJ region. In the present study the EAA without affecting responses evoked by NMDA. This evidence receptor agonists glutamate, NMDA, kainate, and AMPA were suggests that both NMDA and non-NMDA EAA receptor types applied locally to the TMJ region. Jaw muscle responses similar are located within the TMJ region and may contribute to jaw to those evoked by MO application to the TMJ region were muscle activity that can be reflexively evoked from the TMJ achieved with glutamate, NMDA, AMPA, and kainate. Repeated region. application of glutamate, NMDA, or AMPA at intervals of 30 min Key words: digastric muscle; excitatory amino acids; masse- evoked responses in the ipsilateral jaw muscles that were of ter muscle; pain; temporomandibular joint; trigeminal Recently, it has been demonstrated that excitatory amino acid electromyographic activity (Yu et al., 1995). However, increases (EAA) receptors are present not only on dorsal root and trigem- in jaw muscle activity as a result of MO application to the TMJ inal ganglion neurons (Sato et al., 1993; Tachibana et al., 1994; region were attenuated by preapplication of the noncompetitive Pelkey and Marshall, 1995; Sahara et al., 1997) but also on the NMDA receptor antagonist MK-801 into the TMJ. This result peripheral ends of small-diameter primary afferents (Carlton et suggests that part of the action of MO might be mediated through al., 1995) as well as non-neural peripheral tissues (Erdo, 1991). the activation of peripheral NMDA receptors. Whether such receptors have a functional role in translating the The present study was undertaken to investigate whether both features of nociceptive stimuli into neural codes has yet to be NMDA and non-NMDA peripheral EAA receptors are located determined. However, it has been suggested that activation of within the TMJ region. Glutamate and the selective EAA recep- these receptors by local application (e.g., subdermal) of glutamate tor agonists NMDA, kainate, and AMPA were applied to the and selective EAA receptor agonists may result in peripheral TMJ region in an attempt to evoke reflex jaw muscle activity. The sensitization (Carlton et al., 1995; Jackson et al., 1995; Zhou et results show that when applied to the TMJ region in adequate al., 1996; Davidson et al., 1997; Lawand et al., 1997) or even elicit doses, these EAA agonists can increase jaw muscle activity in a nociceptive responses (Ault and Hildebrand, 1993a,b). Further- manner analogous to other algesic chemicals, such as potassium more, it appears that part of the nociceptive mechanisms under- chloride, hypertonic saline, and bradykinin, as well as MO (Bro- lying the actions of inflammatory irritants and algesic chemicals, ton and Sessle, 1988; Yu et al., 1995). EAA receptor agonist- such as mustard oil (MO), may result from the activation of evoked jaw muscle activity can be reduced by antagonists selec- peripheral EAA receptors (Yu et al., 1996). tive for both NMDA and non-NMDA receptors. These results We have presented evidence that peripheral NMDA receptors provide evidence in support of the hypothesis that functional may play a role in mediating increases in jaw muscle activity EAA receptors are located within the TMJ region. resulting from application of inflammatory irritants and algesic A portion of these data has been previously presented in chemicals to the temporomandibular joint (TMJ) region (Yu et abstract form (Cairns et al., 1997). al., 1996). Specifically, local application of the inflammatory irri- tant MO to the rat TMJ region was shown to increase jaw MATERIALS AND METHODS A total of 137 male Sprague Dawley rats (250–450 gm) were prepared for Received April 8, 1998; revised June 26, 1998; accepted July 21, 1998. acute recording of jaw muscle electromyographic (EMG) activity as This research was supported by National Institutes of Health Grant DE11995. We previously described (Hu et al., 1993; Yu et al., 1994, 1995, 1996). Briefly, thank K. MacLeod for electronic services. under surgical anesthesia (O2 , 0.3–0.4 l/min; N2O, 0.6–0.7 l/min; halo- Correspondence should be addressed to Dr. James W. Hu, Faculty of Dentistry, thane, 1.5–2%) a tracheal cannula was inserted, and the left femoral vein The University of Toronto, 124 Edward Street, Toronto, Ontario M5G 1G6, was cannulated. Bipolar electrodes were fashioned out of 36 gauge Canada. Teflon-coated single-strand stainless steel wire and inserted bilaterally Copyright © 1998 Society for Neuroscience 0270-6474/98/188056-09$05.00/0 into the digastric and masseter muscles. The rat’s head was placed in a Cairns et al. • Peripheral Excitatory Amino Acid Receptors J. Neurosci., October 1, 1998, 18(19):8056–8064 8057 stereotaxic frame, the skin over the dorsal surface of the skull was the baseline plus 2 SD was chosen as a signal to noise limit because it reflected, and two screws were inserted into the parietal bone. These represents an approximation of the 95% confidence interval for the mean screws were attached to a vertical support bar with dental acrylic to baseline activity. The relative area under the EMG response curve facilitate access to the TMJ region and thereby allowed the ear bars to be (AUC) was calculated by summing the value of the first and all subse- removed. On removal of the ear bars, the needle tip of a catheter, quent EMG area bins .2 SDs above baseline EMG activity and defined consisting of a 27 gauge needle connected by polyethylene tubing to a as the overall response. Hamilton syringe (50 ml), was carefully inserted into the TMJ region and Significant differences in the relative AUC for multiple applications of used for drug applications. glutamate or other EAA agonists were determined with a repeated In some experiments, an incision was made in the skin over the neck measures ANOVA on ranks ( p , 0.05). Significant differences in the to expose the brainstem and upper cervical spinal cord. A laminectomy relative AUC for paired applications of glutamate or other EAA agonists was performed on the C1 vertebra, and the dura overlying the brainstem were determined with a paired Student’s t test or Wilcoxon signed rank and cervical spinal cord was removed. A 5 ml Hamilton syringe was test ( p , 0.05). All values are expressed as a mean 6 SE. placed in contact with the brainstem and used to apply either lidocaine or Terminal procedures. At the end of each experiment, rats were killed normal saline onto it. with T61 (Hoechst). In some rats treated with MO or glutamate, Evans On completion of the surgery, the anesthetic level was slowly reduced blue dye (6 mg/kg) was injected into the femoral vein 10 min before until noxious pinch of the hindpaw toes produced a slight limb with- killing. After killing the rat, the tissue surrounding the TMJ region was drawal reflex. This was regularly achieved at halothane concentrations of gently dissected out of the way, and a visual examination of the TMJ and 0.7–1.0%. The animal was then maintained at this level of anesthesia for surrounding tissues was made. The presence of any blue staining was the duration of the experiment. Heart rate and core body temperature taken as an indication of plasma protein extravasation into the TMJ were monitored throughout the experiment and maintained within nor- region (Haas et al., 1992; Yu et al., 1995). mal physiological limits. All surgeries and procedures were approved by the University of Toronto Animal Care Committee in accordance with RESULTS the regulations of the Ontario Animal Research Act (Canada). Drug solutions. The following drugs were used in the present study: the Dose–response relationship inflammatory irritant and small-fiber excitant MO (allylisothiocyanate Application of MO to the TMJ region bilaterally in three rats 20% in mineral oil; BDH, Poole, Dorset, UK); the EAA receptor agonists glutamic acid, NMDA, kainic acid, and AMPA; the EAA activated both the ipsilateral and contralateral jaw muscles with a receptor antagonists DL-2-amino-5-phosphonovalerate (APV) and characteristic time course (see example in Fig. 1). The latency to 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX); and lidocaine HCl 1% onset for MO-evoked EMG activity ranged from 3 to 8 sec (mean, (Xylocaine, Astra). EAA receptor agonists and antagonists were ac- 4.8 6 0.4 sec). The mean AUCs were similar to those described quired from Research Biochemicals International (Natick, MA). All previously (Hu et al., 1993). EAA receptor agonists and antagonists were dissolved in isotonic saline, and the resulting solutions were adjusted to a pH of ;7.
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