Primary sensorimotor cortex exhibits complex dependencies of spike-field coherence on neuronal firing rates, field power, and behavior.

Spike-field coherence (SFC) is widely used to assess cortico-cortical interactions during sensorimotor behavioral tasks by measuring the consistency of the relative phases between the spike train of a neuron and the concurrent local field potentials (LFPs). Interpretations of SFC as a measure of functional connectivity are complicated by theoretical work suggesting that estimates of SFC depend on overall neuronal activity. We evaluated the dependence of SFC on neuronal firing rates, LFP power, and behavior in the primary motor (MIo) and primary somatosensory (SIo) areas of the orofacial sensorimotor cortex of monkeys ( Macaca mulatta) during performance of a tongue-protrusion task. Although we occasionally observed monotonically increasing linear relationships between coherence and firing rate, we most often found highly complex, nonmonotonic relationships in both SIo and MIo and sometimes even found that coherence decreased with increasing firing rate. The lack of linear relationships was also true for both LFP power and tongue-protrusive force. Moreover, the ratio between maximal firing rate and the firing rate at peak coherence deviated significantly from unity, indicating that MIo and SIo neurons achieved maximal SFC at a submaximal level of spiking. Overall, these results point to complex relationships of SFC to firing rates, LFP power, and behavior during sensorimotor cortico-cortical interactions: coherence is a measure of functional connectivity whose magnitude is not a mere monotonic reflection of changes in firing rate, LFP power, or the relevantly controlled behavioral parameter. NEW & NOTEWORTHY The concern that estimates of spike-field coherence depend on the firing rates of single neurons has influenced analytical methods employed by experimental studies investigating the functional interactions between cortical areas. Our study shows that the overwhelming majority of the estimated spike-field coherence exhibited complex relations with firing rates of neurons in the orofacial sensorimotor cortex. The lack of monotonic relations was also evident after testing the influence of local field potential power and force on spike-field coherence.

Jaw sensorimotor control in healthy adults and effects of ageing.

The oro-facial sensorimotor system is a unique system significantly distinguished from the spinal sensorimotor system. The jaw muscles are involved in mastication, swallowing and articulatory speech movements and their integration with respiration. These sensorimotor functions are vital for sustaining life and necessitate complex neuromuscular processing to provide for exquisite sensorimotor control of numerous oro-facial muscles. The function of the jaw muscles in relation to sensorimotor control of these movements may be subject to ageing-related declines. This review will focus on peripheral, brainstem and higher brain centre mechanisms involved in reflex regulation and sensorimotor coordination and control of jaw muscles in healthy adults. It will outline the limited literature bearing on age-related declines in jaw sensorimotor functions and control including reduced biting forces and increased risk of impaired chewing, speaking and swallowing. The mechanisms underlying these alterations include age-related degenerative changes within the peripheral neuromuscular system and in brain regions involved in the generation and control of jaw movements. In the light of the vital role of jaw sensorimotor functions in sustaining life, normal ageing involves compensatory mechanisms that utilise the neuroplastic capacity of the brain and the recruitment of additional brain regions involved in sensorimotor performance and closely associated functions (e.g. cognition and memory). However, these regions are themselves susceptible to detrimental age-related changes. Thus, better understanding of the peripheral and central mechanisms underlying age-related sensorimotor impairment is crucial for developing improved treatment approaches to prevent or cure impaired jaw sensorimotor functions and to thereby improve health and quality of life.

Directional information from neuronal ensembles in the primate orofacial sensorimotor cortex.

Neurons in the arm and orofacial regions of the sensorimotor cortex in behaving monkeys display directional tuning of their activity during arm reaching and tongue protrusion, respectively. While studies on population activity abound for the arm motor cortex, how populations of neurons from the orofacial sensorimotor cortex represent direction has never been described. We therefore examined and compared the directional information contained in the spiking activity of populations of single neurons recorded simultaneously from chronically implanted microelectrode arrays in the orofacial primary motor (MIo, N = 345) and somatosensory (SIo, N = 336) cortices of monkeys (Macaca mulatta) as they protruded their tongue in different directions. Differential modulation to the direction of tongue protrusion was found in >60% of task-modulated neurons in MIo and SIo and was stronger in SIo (P < 0.05). Moreover, mutual information between direction and spiking was significantly higher in SIo compared with MIo at force onset and force offset (P < 0.01). Finally, the direction of tongue protrusion was accurately predicted on a trial-by-trial basis from the spiking activity of populations of MIo or SIo neurons by using a discrete decoder (P < 0.01). The highly reliable decoding was comparable between MIo and SIo neurons. However, the temporal evolution of the decoding performance differed between these two areas: MIo showed late-onset, fast-rising, and phasic performance, whereas SIo exhibited early-onset, slow-rising, and sustained performance. Overall, the results suggest that both MIo and SIo are highly involved in representing the direction of tongue protrusion but they differ in the amplitude and temporal processing of the directional information distributed across populations of neurons.

Development of a model to investigate the effects of prolonged ischaemia on the muscles of mastication of male Sprague Dawley rats.

OBJECTIVE: The aims of this study were to develop a novel rodent model of masticatory muscle ischaemia via unilateral ligation of the external carotid artery (ECA), and to undertake a preliminary investigation to characterize its downstream effects on mechanosensitivity and cellular features of the masseter and temporalis muscles. DESIGN: The right ECA of 18 male Sprague-Dawley rats was ligated under general anaesthesia. Mechanical detection thresholds (MDTs) at the masseter and temporalis bilaterally were measured immediately before ECA ligation and after euthanasia at 10-, 20-, and 35-days (n = 6 rats/timepoint). Tissue samples from both muscles and sides were harvested for histological analyses and for assessing changes in the expression of markers of hypoxia and muscle degeneration (Hif-1α, VegfA, and Fbxo32) via real time PCR. Data were analyzed using mixed effect models and non-parametric tests. Statistical significance was set at p < 0.05. RESULTS: MDTs were higher in the right than left hemiface (p = 0.009) after 20 days. Histological changes indicative of muscle degeneration and fibrosis were observed in the right muscles. Hif-1α, VegfA, and Fbxo32 were more highly expressed in the masseter than temporalis muscles (all p < 0.05). Hif-1α and, VegfA did not change significantly with time in all muscles (all p > 0.05). Fbxo32 expression gradually increased in the right masseter (p = 0.024) and left temporalis (p = 0.05). CONCLUSIONS: ECA ligation in rats induced hyposensitivity in the homolateral hemiface after 20 days accompanied by tissue degenerative changes. Our findings support the use of this model to study pathophysiologic mechanisms of masticatory muscle ischaemia in larger investigations.

Role of astrocytes in pain.

Over the last decade, a series of studies has demonstrated that glia in the central nervous system play roles in many aspects of neuronal functioning including pain processing. Peripheral tissue damage or inflammation initiates signals that alter the function of the glial cells (microglia and astrocytes in particular), which in turn release factors that regulate nociceptive neuronal excitability. Like immune cells, these glial cells not only react at sites of central and/or peripheral nervous system damage but also exert their action at remote sites from the focus of injury or disease. As well as extensive evidence of microglial involvement in various pain states, there is also documentation that astrocytes are involved, sometimes seemingly playing a more dominant role than microglia. The interactions between astrocytes, microglia and neurons are now recognized as fundamental mechanisms underlying acute and chronic pain states. This review focuses on recent advances in understanding of the role of astrocytes in pain states.

From brain to bridge: masticatory function and dental implants.

Masticatory function is an important aspect of oral health, and oral rehabilitation should aim to maintain or restore adequate function. The present qualitative review is the joint effort of a group of clinicians and researchers with experiences ranging from basic and clinical oral neuroscience to management of patients with dental implants. The aim is to provide a short summary for the clinician of the many aspects related to masticatory function (including quality of life) and rehabilitation with dental implants. While there are many reviews on the tissue responses to dental implants and technical aspects, the functional aspects have received relatively little focus.

Modulation of astroglial glutamine synthetase activity affects nociceptive behaviour and central sensitization of medullary dorsal horn nociceptive neurons in a rat model of chronic pulpitis.

Previous studies indicate that the astroglial glutamate-glutamine shuttle may be involved in acute pulpal inflammatory pain by influencing central sensitization induced in nociceptive neurons in the trigeminal subnucleus caudalis [the medullary dorsal horn (MDH)] by application of an inflammatory irritant to the rat tooth pulp. The aim of this study was to test if intrathecal application to the rat medulla of the astroglial glutamine synthetase inhibitor methionine sulfoximine (MSO) can influence the central sensitization of MDH nociceptive neurons and the animal's associated behaviour that are manifested in a model of chronic pulpitis pain induced by exposure of a mandibular molar pulp. This model was found to be associated with nocifensive behaviour and enhanced reflex activity evoked by mechanical stimulation of the rat's facial skin and with immunocytochemical evidence of astroglial activation in the MDH. These features were apparent for up to 28 days post-operatively. During this post-operative period, the nocifensive behaviour and enhanced reflex activity were significantly attenuated by intrathecal application of MSO (5 µL, 10 mM) but not by vehicle application. In electrophysiological recordings of nociceptive neuronal activity in the MDH, central sensitization was also evident in pulp-exposed rats but not in intact rats and could be significantly attenuated by MSO application but not by vehicle application. These behavioural and neuronal findings suggest that the astroglial glutamate-glutamine shuttle is responsible for the maintenance of inflammation-induced nocifensive behavioural changes and the accompanying central sensitization in MDH nociceptive neurons in this chronic pulpitis pain model.

The effects of training time, sensory loss and pain on human motor learning.

This study determined, in humans, the effects of (i) the number of within-session task repetitions (72 or 144 over a period of 15 or 30 min, respectively) on the time course of motor learning in a long-term (seven consecutive daily motor-training sessions and a 1-week post-follow-up) novel tongue-task training regime and (ii) somatosensory manipulations (capsaicin-induced intra-oral pain or lidocaine-induced sensory loss of the tongue tip) on motor learning in a short-term (single motor-training session consisting of 72 within-session task repetitions over a period of 15 min) novel tongue-task training regime. Novel tongue-task training consisted of tracking a moving target box by generating a pre-set amount of tongue-protrusion force onto a force lever. Analysis of motor behaviour revealed (i) a higher within-session gain for the 30-min tongue-task training regime, but this difference did not differentially affect the time course of the overall motor performance or additional motor performance variables between the 15- and 30-min tongue-task training regimes in subsequent training sessions. (ii) somatosensory manipulations of the tongue tip reduced the gains in overall motor performance, and this reduced motor performance was mainly characterized by exaggerated undershoot errors and delayed reaction times for the lidocaine tongue-task training regime and exaggerated overshoot and undershoot errors as well as delayed reaction times for the capsaicin tongue-task training regime. It is concluded that extended within-session task repetitions do not facilitate additional long-term gains in overall motor performance and intra-oral sensory loss or pain hinders motor learning.

"Tactile" stimulus intensity: information transmission by relay neurons in different trigeminal nuclei.

Comparison of the information transmitted about the intensity of a steady "tactile" stimulus applied to facial skin by single trigemino-thalamic neurons in nucleus oralis and nucleus caudalis indicates that little information loss occurs at the medial lemniscal synaptic relay (nucleus oralis), but that it is gross within the nucleus caudalis.

The Evolution of Neuroscience as a Research Field Relevant to Dentistry.

The field of neuroscience did not exist as such when the Journal of Dental Research was founded 100 y ago. It has emerged as an important scientific field relevant to dentistry in view of the many neurally based functions manifested in the orofacial area (e.g., pain, taste, chewing, swallowing, salivation). This article reviews many of the novel insights that have been gained through neuroscience research into the neural basis of these functions and their clinical relevance to the diagnosis and management of pain and sensorimotor disorders. These include the neural pathways and brain circuitry underlying each of these functions and the role of nonneural as well as neural processes and their "plasticity" in modulating these functions and allowing for adaptation to tissue injury and pain and for learning or rehabilitation of orofacial functions.

(-)-α-Bisabolol reduces nociception and trigeminal central sensitisation in acute orofacial neuropathic pain induced by infraorbital nerve injury.

Neuropathic orofacial pain conditions represent a challenge to diagnose and treat. Natural substances are promising therapeutic options for the control of pain. AIMS: This study aimed to examine whether (-)-α-bisabolol (BISA), a natural terpene, can attenuate nociceptive behaviour and central sensitisation in a rodent model of trigeminal neuropathic pain. MATERIALS AND METHODS: Infraorbital nerve transection (IONX) or sham operation was performed in adult male rats. Head withdrawal thresholds as a measure of facial mechanical sensitivity were tested with von Frey monofilaments applied bilaterally to the facial vibrissal pad pre-operatively (baseline) and then post-operatively before and at 60, 120, 240 and 360 min after administration of vehicle control per oris (p.o.) or BISA (200 mg/kg p.o.) (n = 8/group). Effects of BISA or vehicle on the activity of nociceptive neurons recorded in the medullary dorsal horn (MDH) were tested on post - operative day 8-10. ANOVA followed by post-hoc Bonferroni tested for statistically significant differences (p < 0.05) across study groups and time points. KEY FINDINGS: IONX animals (but not sham or naïve animals) showed post-operative facial mechanical hypersensitivity that was unaffected by vehicle. However, administration of BISA at post-operative day 7 significantly reversed the mechanical hypersensitivity in IONX rats; this effect lasted for at least 6 h. BISA also attenuated IONX-induced central sensitisation of MDH nociceptive neurons, as reflected in reversal of their reduced activation thresholds, increased responses to graded mechanical stimuli and enhanced spontaneous activity. SIGNIFICANCE: BISA may attenuate nociceptive behaviour and central sensitisation in a rat model of acute trigeminal neuropathic pain.

Surgical incision can alter capsaicin-induced central sensitization in rat brainstem nociceptive neurons.

Surgical trauma can affect spinal neuronal excitability, but there have been no studies of the effects of surgical cutaneous injury on central nociceptive processing of deep afferent inputs evoked by noxious stimuli such as capsaicin. Thus our aim was to test the effect of surgical cutaneous incision in influencing central sensitization induced by capsaicin injection into the temporomandibular joint (TMJ). The activity of single nociceptive neurons activated by noxious mechanical stimulation of the TMJ was recorded in the trigeminal subnucleus caudalis/upper cervical cord of halothane-anesthetized rats. The cutaneous mechanoreceptive field (RF), cutaneous mechanical activation threshold (MAT) and TMJ MAT of neurons before and after both surgical cutaneous incision alone and capsaicin injection were compared with results of incision and lidocaine pretreatment of the facial skin overlying the TMJ and capsaicin injection into the TMJ. Incision itself induced a barrage of neuronal spikes and excitability increases reflecting central sensitization (cutaneous RF expansion, cutaneous MAT reduction) in most neurons tested whereas lidocaine pretreatment significantly attenuated the barrage and central sensitization. Capsaicin injection into the TMJ induced cutaneous RF expansion, cutaneous MAT reduction and TMJ MAT reduction following lidocaine pretreatment of the cutaneous incision site whereas capsaicin injection following incision alone not only failed to induce further central sensitization but also decreased the existing incision-induced central sensitization (no cutaneous RF expansion, increased cutaneous MAT and TMJ MAT) in most neurons tested. These findings suggest that central sensitization induced by capsaicin alone or by cutaneous incision alone can readily occur in TMJ-responsive nociceptive neurons and that following incision-induced excitability increases, capsaicin may result in a temporary suppression of nociceptive neuronal changes reflecting central sensitization.

Effects of noxious stimulation of orofacial tissues on rat licking behaviour.

OBJECTIVE: Since there is limited information of the effects of orofacial pain on oromotor behaviour, the aim of this study was to test the effects of injection of the algesic chemical glutamate into orofacial tissues on licking behaviour in rats. DESIGN: Male Sprague-Dawley rats were trained to carry out stereotyped licking from a water spout connected to a force transducer, and once they met preset licking motor requirements (peak force of licking of 2-20 g, interlick interval of 0.11-0.19s), their masseter muscle or tongue was injected with either isotonic saline (0.9%, 5 microL) or glutamate (1.0M, 5 microL) and several parameters of their licking performance were re-assessed. RESULTS: There were significant effects (P<0.05; 1-way repeated measures ANOVA) of glutamate injection into the tongue on the number of clusters of licks, the number of licks per cluster, the intercluster period, the peak force of licking and the interlick interval, but there were no significant (P>0.05) effects on licking of isotonic saline injection into the tongue or isotonic saline or glutamate injection into the masseter muscle. CONCLUSIONS: These findings provide the first documentation that noxious stimulation of the tongue, but not of the masseter muscle, has a modulatory effect on licking behaviour in the rat and suggest that the neural substrate for licking may be sensitive to selective nociceptive inputs from the orofacial region.

Relationships between craniofacial pain and bruxism.

A still commonly held view in the literature and clinical practice is that bruxism causes pain because of overloading of the musculoskeletal tissue and craniofacial pain, on the other hand, triggers more bruxism. Furthermore, it is often believed that there is a dose-response gradient so that more bruxism (intensity, duration) leads to more overloading and pain. Provided the existence of efficient techniques to treat bruxism, it would be straightforward in such a simple system to target bruxism as the cause of pain and hence treat the pain. Of course, human biological systems are much more complex and therefore, it is no surprise that the relationship between bruxism and pain is far from being simple or even linear. Indeed, there are unexpected relationships, which complicate the establishment of adequate explanatory models. Part of the reason is the complexity of the bruxism in itself, which presents significant challenges related to operationalized criteria and diagnostic tools and underlying pathophysiology issues, which have been dealt with in other reviews in this issue. However, another important reason is the multifaceted nature of craniofacial pain. This review will address our current understanding of classification issues, epidemiology and neurobiological mechanisms of craniofacial pain. Experimental models of bruxism may help to further the understanding of the relationship between craniofacial pain and bruxism in addition to insights from intervention studies. The review will enable clinicians to understand the reasons why simple cause-effect relationships between bruxism and craniofacial pain are inadequate and the current implications for management of craniofacial pain.

Localization of P2X2 and P2X3 receptors in rat trigeminal ganglion neurons.

Purine receptors have been implicated in central neurotransmission from nociceptive primary afferent neurons, and ATP-mediated currents in sensory neurons have been shown to be mediated by both P2X3 and P2X2/3 receptors. The aim of the present study was to quantitatively examine the distribution of P2X2 and P2X3 receptors in primary afferent cell bodies in the rat trigeminal ganglion, including those innervating the dura. In order to determine the classes of neurons that express these receptor subtypes, purine receptor immunoreactivity was examined for colocalization with markers of myelinated (neurofilament 200; NF200) or mostly unmyelinated, non-peptidergic fibers (Bandeiraea simplicifolia isolectin B4; IB4). Forty percent of P2X2 and 64% of P2X3 receptor-expressing cells were IB4 positive, and 33% of P2X2 and 31% of P2X3 receptor-expressing cells were NF200 positive. Approximately 40% of cells expressing P2X2 receptors also expressed P2X3 receptors and vice versa. Trigeminal ganglion neurons innervating the dura mater were retrogradely labeled and 52% of these neurons expressed either P2X2 or P2X3 or both receptors. These results are consistent with electrophysiological findings that P2X receptors exist on the central terminals of trigeminal afferent neurons, and provide evidence that afferents supplying the dura express both receptors. In addition, the data suggest specific differences exist in P2X receptor expression between the spinal and trigeminal nociceptive systems.

Sex-related differences in NMDA-evoked rat masseter muscle afferent discharge result from estrogen-mediated modulation of peripheral NMDA receptor activity.

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.

Neuroplasticity of face primary motor cortex control of orofacial movements.

We have carried out a series of studies to address the role of the face primary motor area (MI) in the cerebral cortex in trained or semi-automatic orofacial motor behaviours and in behavioural adaptations to an altered oral environment. These studies have utilized intracortical microstimulation (ICMS), reversible cold block or single neurone recordings in face MI. Our studies in monkeys have revealed that face MI plays a strategic role in elemental and learned motor behaviours and in certain aspects of chewing and swallowing. Furthermore, successful training of awake monkeys in a novel tongue-protrusion task is associated with significant neuroplastic changes in face MI. These findings in monkeys are supported by correlated findings in humans which have revealed significantly enhanced corticomotoneuronal excitability when humans learn the novel tongue-protrusion task. Our related ICMS studies in rats reveal that trimming or extraction of the rat's lower incisors or damage to the rat's lingual nerve can result in significant changes in the MI representations of the tongue or jaw muscles. These various findings suggest that the face MI is important in orofacial motor skill acquisition and adaptation to an altered occlusion or loss of teeth or lingual sensory function, and that it reflects dynamic and modifiable constructs that are modelled by behaviourally significant experiences and that are critical to learning and adaptive processes.

Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society.

Neuropathic pain (NeP), generated by disorders of the peripheral and central nervous system, can be particularly severe and disabling. Prevalence estimates indicate that 2% to 3% of the population in the developed world suffer from NeP, which suggests that up to one million Canadians have this disabling condition. Evidence-based guidelines for the pharmacological management of NeP are therefore urgently needed. Randomized, controlled trials, systematic reviews and existing guidelines focusing on the pharmacological management of NeP were evaluated at a consensus meeting. Medications are recommended in the guidelines if their analgesic efficacy was supported by at least one methodologically sound, randomized, controlled trial showing significant benefit relative to placebo or another relevant control group. Recommendations for treatment are based on degree of evidence of analgesic efficacy, safety, ease of use and cost-effectiveness. Analgesic agents recommended for first-line treatments are certain antidepressants (tricyclics) and anticonvulsants (gabapentin and pregabalin). Second-line treatments recommended are serotonin noradrenaline reuptake inhibitors and topical lidocaine. Tramadol and controlled-release opioid analgesics are recommended as third-line treatments for moderate to severe pain. Recommended fourth-line treatments include cannabinoids, methadone and anticonvulsants with lesser evidence of efficacy, such as lamotrigine, topiramate and valproic acid. Treatment must be individualized for each patient based on efficacy, side-effect profile and drug accessibility, including cost. Further studies are required to examine head-to-head comparisons among analgesics, combinations of analgesics, long-term outcomes, and treatment of pediatric and central NeP.

Sensitivity of rat temporalis muscle afferent fibers to peripheral N-methyl-D-aspartate receptor activation.

The temporalis muscle is a common source of pain in headache and chronic craniofacial pain conditions such as temporomandibular disorders, which have an increased prevalence in women. The characteristics of slowly conducting temporalis afferent fibers have not been investigated. Therefore, the aim of the present study was to examine the characteristics of slowly conducting temporalis muscle afferent fibers and to determine whether these fibers are excited by activation of peripheral N-methyl-D-aspartate receptors. The response properties of a total of 117 temporalis afferent fibers were assessed in male and female rats. A majority of these fibers had high mechanical thresholds and slow conduction velocities (<10 m/s). The mechanical threshold of the temporalis afferent fibers was inversely correlated with afferent conduction velocity, however, no sex-related differences in mechanical threshold were identified. There were also no sex-related differences in N-methyl-D-aspartate-evoked afferent discharge. Indeed, injection of a high concentration (1600 mM) of N-methyl-D-aspartate into the temporalis muscle was necessary to evoke significant afferent discharge. Thirty minutes after the initial injection of N-methyl-D-aspartate into the temporalis muscle, a second injection of N-methyl-D-aspartate produced a response only about 50% as large as the initial injection. Co-injection of ketamine (20 mM) with the second injection of N-methyl-D-aspartate significantly decreased N-methyl-D-aspartate-evoked afferent discharge in both sexes. This concentration of ketamine is greater than that needed to attenuate afferent discharge evoked by injection of glutamate into the masseter muscle. These results suggest that unlike masseter afferent fibers, temporalis afferent fibers are relatively insensitive to peripheral N-methyl-D-aspartate receptor activation.

Central sensitization in thalamic nociceptive neurons induced by mustard oil application to rat molar tooth pulp.

We have recently demonstrated that application of mustard oil (MO), a small-fiber excitant and inflammatory irritant, to the rat maxillary molar tooth pulp induces central sensitization that is reflected in changes in spontaneous activity, mechanoreceptive field (RF) size, mechanical activation threshold, and responses to graded mechanical stimuli applied to the neuronal RF in trigeminal brainstem subnucleus caudalis and subnucleus oralis. The aim of this study was to test whether central sensitization can be induced in nociceptive neurons of the posterior thalamus by MO application to the pulp. Single unit neuronal activity was recorded in the ventroposterior medial nucleus (VPM) or posterior nuclear group (PO) of the thalamus in anesthetized rats, and nociceptive neurons were classified as wide dynamic range (WDR) or nociceptive-specific (NS). MO application to the pulp was studied in 47 thalamic nociceptive neurons and found to excite over 50% of the 35 VPM neurons tested and to produce significant long-lasting (over 40 min) increases in spontaneous activity, cutaneous pinch RF size and responses to graded mechanical stimuli, and a decrease in threshold in the 29 NS neurons tested; a smaller but statistically significant increase in mean spontaneous firing rate and decrease in activation threshold occurred following MO in the six WDR neurons tested. Vehicle application to the pulp did not produce any significant changes in six VPM NS neurons tested. MO application to the pulp produced pronounced increases in spontaneous activity, pinch RF size, and responses to mechanical stimuli, and a decrease in threshold in three of the six PO neurons. In conclusion, application of the inflammatory irritant MO to the tooth pulp results in central sensitization of thalamic nociceptive neurons and this neuronal hyperexcitability likely contributes to the behavioral consequences of peripheral inflammation manifesting as pain referral, hyperalgesia and allodynia.