Trigeminal Sensory Complex Research Articles

Specificities of orofacial neuropathic pain

Head pain and notably orofacial pain differs from spinal pain on pathophysiological, clinical, therapeutic and prognostic levels. Its high prevalence, important impact on quality of life and significant socio-economical burden justify specific study of such type of pain. Among them, neuropathic orofacial pain resulting from disease or trauma of the trigeminal nervous system is among the most difficult types of pain to diagnose and to treat. Deciphering of underlying peripheral and central mechanisms has allowed numerous conceptual, clinical and therapeutic advances, notably the role of neural and non neural cell types, such as glia, immunocytes, vascular endothelial cells or the role of trigeminal sensory complex neural circuitry reconfiguration in the development of post-traumatic trigeminal neuropathic pain. Cellular interactions within the trigeminal ganglion, allowing a better understanding of several painful dental, ocular or cephalalgic comorbidities, are also described.

Macaque monkey trigeminal blink reflex circuits targeting levator palpebrae superioris motoneurons.

For normal viewing, the eyes are held open by the tonic actions of the levator palpebrae superioris (levator) muscle raising the upper eyelid. This activity is interrupted during blinks, when the eyelid sweeps down to spread the tear film or protect the cornea. We examined the circuit connecting the principal trigeminal nucleus to the levator motoneurons by use of both anterograde and retrograde tracers in macaque monkeys. Injections of anterograde tracer were made into the principal trigeminal nucleus using either a stereotaxic approach or localization following physiological characterization of trigeminal second order neurons. Anterogradely labeled axonal arbors were located both within the caudal central subdivision, which contains levator motoneurons, and in the adjacent supraoculomotor area. Labeled boutons made synaptic contacts on retrogradely labeled levator motoneurons indicating a monosynaptic connection. As the eye is also retracted through the actions of the rectus muscles during a blink, we examined whether these trigeminal injections labeled boutons contacting rectus motoneurons within the oculomotor nucleus. These were not found when the injection sites were confined to the principal trigeminal nucleus region. To identify the source of the projection to the levator motoneurons, we injected retrograde tracer into the oculomotor complex. Retrogradely labeled cells were confined to a narrow, dorsoventrally oriented cell population that lined the rostral edge of the principal trigeminal nucleus. Presumably these cells inhibit levator motoneurons, while other parts of the trigeminal sensory complex are activating orbicularis oculi motoneurons, when a blink is initiated by sensory stimuli contacting the face.

Macaque monkey trigeminal blink reflex circuits targeting orbicularis oculi motoneurons.

The trigeminal blink reflex plays an important role in protecting the corneal surface from damage and preserving visual function in an unpredictable environment. The closing phase of the human reflex, produced by activation of the orbicularis oculi (ObOc) muscles, consists of an initial, small, ipsilateral R1 component, followed by a larger, bilateral R2 component. We investigated the circuitry that underlies this reflex in macaque (Macaca fascicularis and Macaca mulatta) monkeys by the use of single and dual tracer methods. Injection of retrograde tracer into the facial nucleus labeled neurons in the principal trigeminal nucleus, and in the spinal nucleus pars oralis and interpolaris, bilaterally, and in pars caudalis, ipsilaterally. Injection of anterograde tracer into the principal trigeminal nucleus labeled axons that directly terminated on ObOc motoneurons, with an ipsilateral predominance. Injection of anterograde tracer into pars caudalis of the spinal trigeminal nucleus labeled axons that directly terminated on ipsilateral ObOc motoneurons. The observed pattern of labeling indicates that the reticular formation ventromedial to the principal and spinal nuclei also contributes extensive bilateral input to ObOc motoneurons. Thus, much of the trigeminal sensory complex is in a position to supply a monosynaptic drive for lid closure, and the adjacent reticular formation can supply a disynaptic drive. These findings indicate that the assignment of the R1 and R2 components of the blink reflex to different parts of the trigeminal sensory complex cannot be exclusively based on subdivision connectional relationships with facial motoneurons. The characteristics of the R2 component may be due, instead, to other circuit properties.

Morphological and Functional Changes of Corneal Nerves and Their Contribution to Peripheral and Central Sensory Abnormalities.

The cornea is the most densely innervated and sensitive tissue in the body. The cornea is exclusively innervated by C- and A-delta fibers, including mechano-nociceptors that are triggered by noxious mechanical stimulation, polymodal nociceptors that are excited by mechanical, chemical, and thermal stimuli, and cold thermoreceptors that are activated by cooling. Noxious stimulations activate corneal nociceptors whose cell bodies are located in the trigeminal ganglion (TG) and project central axons to the trigeminal brainstem sensory complex. Ocular pain, in particular, that driven by corneal nerves, is considered to be a core symptom of inflammatory and traumatic disorders of the ocular surface. Ocular surface injury affecting corneal nerves and leading to inflammatory responses can occur under multiple pathological conditions, such as chemical burn, persistent dry eye, and corneal neuropathic pain as well as after some ophthalmological surgical interventions such as photorefractive surgery. This review depicts the morphological and functional changes of corneal nerve terminals following corneal damage and dry eye disease (DED), both ocular surface conditions leading to sensory abnormalities. In addition, the recent fundamental and clinical findings of the importance of peripheral and central neuroimmune interactions in the development of corneal hypersensitivity are discussed. Next, the cellular and molecular changes of corneal neurons in the TG and central structures that are driven by corneal nerve abnormalities are presented. A better understanding of the corneal nerve abnormalities as well as neuroimmune interactions may contribute to the identification of a novel therapeutic targets for alleviating corneal pain.

Spinal trigeminal subnucleus pars muralis: An interface for apneic reflex

Noxious stimulation of the nasal cavity elicits protective reflexes for the upper respiratory tract, including sneezing, mucus secretion, apnea and cardiovascular reflexes. Yet, no studies have shown the full circuit responsible for the apneic response upon noxious stimulation of the nasal mucosa. Here, we show that injection of cholera toxin beta subunit into the nasal mucosa leads to terminal labeling in the transition zone between the interpolaris and caudalis subnuclei of the trigeminal sensory complex, i.e. subnucleus muralis (SpVm). We also provide physiological evidence that ammonia vapor delivered into the nasal cavity induces an apneic reaction and activates some SpVm cells. Subnucleus muralis cells also respond to mechanical stimulation of the narial pad and the nasal mucosa. Yet, none of the muralis cells responded to vibrissa deflection. Electrolytic lesion of SpVm or unilateral transection of the anterior ethmoidal nerve prevent apnea induced by ammonia delivery to the nasal epithelium, demonstrating their crucial role in the apneic reflex. We also found direct projections from SpVm to the respiratory centers, particularly the preBötzinger complex (preBötC). Inhibition of inspiratory preBötC cells and increased firing of expiratory preBötC cells are associated with ammonia‐induced apnea.Anatomical and physiological data presented here support the hypothesis that nasal induced apnea may be mediated by direct projections from nasal innervated Subnucleus muralis neurons to the PreBötC complex.

Chronic dry eye induced corneal hypersensitivity, neuroinflammatory responses, and synaptic plasticity in the mouse trigeminal brainstem

BackgroundDry eye disease (DED) is a multifactorial disease associated with ocular surface inflammation, pain, and nerve abnormalities. We studied the peripheral and central neuroinflammatory responses that occur during persistent DED using molecular, cellular, behavioral, and electrophysiological approaches.MethodsA mouse model of DED was obtained by unilateral excision of the extraorbital lachrymal gland (ELG) and Harderian gland (HG) of adult female C57BL/6 mice. In vivo tests were conducted at 7, 14, and 21 days (d) after surgery. Tear production was measured by a phenol red test and corneal alterations and inflammation were assessed by fluorescein staining and in vivo confocal microscopy. Corneal nerve morphology was evaluated by nerve staining. Mechanical corneal sensitivity was monitored using von Frey filaments. Multi-unit extracellular recording of ciliary nerve fiber activity was used to monitor spontaneous corneal nerve activity. RT-qPCR and immunostaining were used to determine RNA and protein levels at d21.ResultsWe observed a marked reduction of tear production and the development of corneal inflammation at d7, d14, and d21 post-surgery in DED animals. Chronic DE induced a reduction of intraepithelial corneal nerve terminals. Behavioral and electrophysiological studies showed that the DED animals developed time-dependent mechanical corneal hypersensitivity accompanied by increased spontaneous ciliary nerve fiber electrical activity. Consistent with these findings, DED mice exhibited central presynaptic plasticity, demonstrated by a higher Piccolo immunoreactivity in the ipsilateral trigeminal brainstem sensory complex (TBSC). At d21 post-surgery, mRNA levels of pro-inflammatory (IL-6 and IL-1β), astrocyte (GFAP), and oxidative (iNOS2 and NOX4) markers increased significantly in the ipsilateral trigeminal ganglion (TG). This correlated with an increase in Iba1, GFAP, and ATF3 immunostaining in the ipsilateral TG of DED animals. Furthermore, pro-inflammatory cytokines (IL-6, TNFα, IL-1β, and CCL2), iNOS2, neuronal (ATF3 and FOS), and microglial (CD68 and Itgam) markers were also upregulated in the TBSC of DED animals at d21, along with increased immunoreactivity against GFAP and Iba1.ConclusionsOverall, these data highlight peripheral sensitization and neuroinflammatory responses that participate in the development and maintenance of dry eye-related pain. This model may be useful to identify new analgesic molecules to alleviate ocular pain.

Proceedings #21: Specific Patterns of Current Flow Generated by Different tDCS Montages in the Midbrain and in the Trigeminal Brainstem Sensory Nuclear Complex

Proceedings #21: Specific Patterns of Current Flow Generated by Different tDCS Montages in the Midbrain and in the Trigeminal Brainstem Sensory Nuclear Complex

Parallel Inhibitory and Excitatory Trigemino-Facial Feedback Circuitry for Reflexive Vibrissa Movement

Animals employ active touch to optimize the acuity of their tactile sensors. Prior experimental results and models lead to the hypothesis that sensory inputs are used in a recurrent manner to tune the position of the sensors. A combination of electrophysiology, intersectional genetic viral labeling and manipulation, and classical tracing allowed us to identify second-order sensorimotor loops that control vibrissa movements by rodents. Facial motoneurons that drive intrinsic muscles to protract the vibrissae receive a short latency inhibitory input, followed by synaptic excitation, from neurons located in the oralis division of the trigeminal sensory complex. In contrast, motoneurons that retract the mystacial pad and indirectly retract the vibrissae receive only excitatory input from interpolaris cellsthat further project to the thalamus. Silencing this feedback alters retraction. The observed pull-push circuit at the lowest-level sensorimotor loop provides a mechanism for the rapid modulation ofvibrissa touch during exploration of peri-personal space.

The sensory trigeminal complex and the organization of its primary afferents in the zebra finch (Taeniopygia guttata).

Our knowledge of the avian sensory trigeminal system has been largely restricted to the principal trigeminal nucleus (PrV) and its ascending projections to the forebrain. Studies addressing the cytoarchitecture and organization of afferent input to the sensory trigeminal complex, which includes both the PrV and the nuclei of the descending trigeminal tract (nTTD), have only been performed in pigeons and ducks. Here we extend such an analysis to a songbird, the zebra finch (Taeniopygia guttata). We describe the cytoarchitecture of the sensory trigeminal complex, the patterns of calbindin-like and substance P-like immunoreactivity, and the organization of afferents from the three branches of the trigeminal nerve and from the lingual branch of the hypoglossal nerve. On the basis of cytoarchitecture and immunohistochemistry, the sensory trigeminal column can be subdivided from caudal to rostral, as in other species, into cervical dorsal horn, subnucleus caudalis, subnucleus interpolaris, subnucleus oralis, and nucleus principalis. The relative positions of the terminal fields of the three trigeminal branches move from medial to lateral in the dorsal horn to dorsomedial to ventrolateral in nTTD, whereas in PrV there is considerable overlap of mandibular and ophthalmic terminal fields, with only a small maxillary input ventrally. The hypoglossal afferents, which terminate medially in the dorsal horn and dorsolaterally in nTTD, terminate in specific cell groups in the dorsolateral nTTDo and in PrV. This work sets the grounds for further analyses of the ascending connections of the nTTD and the afferents from the syrinx to the trigeminal sensory column.

Abstract # 1835 Corneal injury induces trigeminal pain, peripheral and central neuroinflammatory process

Ocular surface diseases are among the most frequent ocular pathologies, with prevalence ranging from 20% of the general population. Ocular pain following corneal injury is frequently observed in clinic. Here we characterized the peripheral and central neuroinflammatory process in the trigeminal pathways in response to ocular pain. We used topical instillations of 0.2% benzalkonium chloride (BAC) in mice for 7 days. BAC-treated animals developed severe dry eye (reduced tear production and inflammation in the cornea). Hypertonic saline-evoked eye wipe behavior was enhanced in BAC-treated animals. We reported an increased ATF3, FOS and Iba1 immunoreactivity and higher IL-6 and TNF- α mRNA levels in the trigeminal ganglion. Interestingly, the sensory trigeminal complex at the ipsilateral interpolaris/caudalis (Vi/Vc) transition and Vc/upper cervical cord (Vc/C1) regions exhibited higher FOS and Iba1 positive cells in BAC animals. Activated microglial cells were tightly wrapped around activated FOS neurons in both regions. Furthermore, phosphorylated p38 MAPK was markedly enhanced in microglial cells during ocular inflammation. These neuroanatomical data correlated with the increase in mRNA expression of pro-inflammatory (TNF- α , IL-6, CCL2) and neuronal (FOS and ATF3) markers. This work provides the demonstration that corneal inflammation provokes central neuroinflammatory process. Thus, altered activity in intracellular signaling caused by ocular inflammation might play a priming role in the central sensitization of ocular related brainstem circuits, which represents a significant factor in ocular pain development.

Facialis vírusinokuláció fertőzi a vestibularis és cochlearis agyidegmagokat

Background and purpose – There is growing evidence for the viral origin of the Bell’s facial palsy, vestibular neuritis and sudden sensorineural hearing loss, however their exact pathophysiology is still unknown. We investigated the possibility of brainstem infections following peripheral viral inoculations in rats. Methods – Pseudorabies virus, a commonly used neurotropic viral retrograde tracer was injected into the nasolabial region of rats. Five and 6 days after injections, infected brainstem nuclei were demonstrated by immunohistochemical techniques. Results – Infected neurons were found in the motor facial, the medial vestibular, and the sensory trigeminal nuclei, as well as in the medial nucleus of the trapezoid body. Conclusion – Pseudorabies virus infects auditory and vestibular sensory neurons in the brainstem through facial inoculation. The possible routes of infections: 1. trans-synaptic spread constituted by facio-vestibular anastomoses: primarily infected motor facial neuron infects neurons in the medial vestibular nucleus, 2. via trigeminal sensory nerves: the sensory trigeminal complex innervated by GABAergic medial vestibular neurons, and 3. one bisynaptical route: infected facial motoneurons may receive indirect input from the medial vestibular nucleus and the trapezoid body via connecting neurons in the sensory trigeminal complex. We may assume that latent infections of these areas may precede the infections of the peripheral organs and the reactivation of the virus exerts the symptoms.

Ocular inflammation induces trigeminal pain, peripheral and central neuroinflammatory mechanisms

Ocular surface diseases are among the most frequent ocular pathologies, with prevalence ranging from 20% of the general population. In addition, ocular pain following corneal injury is frequently observed in clinic. The aim of the study was to characterize the peripheral and central neuroinflammatory process in the trigeminal pathways in response to cornea alteration induced by chronic topical instillations of 0.2% benzalkonium chloride (BAC) in male C57BL/6J mice. In vitro BAC induced neurotoxicity and increases neuronal (FOS, ATF3) and pro-inflammatory (IL-6) markers in primary mouse trigeminal ganglion culture. BAC-treated mice exhibited 7days after the treatment reduced aqueous tear production and increased inflammatory cell infiltration in the cornea. Hypertonic saline-evoked eye wipe behavior was enhanced in BAC-treated animals that exhibited increased FOS, ATF3 and Iba1 immunoreactivity in the trigeminal ganglion. Ocular inflammation is associated with a significant increase in IL-6 and TNF-α mRNA expression in the trigeminal ganglion. We reported a strong increase in FOS and Iba1 positive cells in particular in the sensory trigeminal complex at the ipsilateral interpolaris/caudalis (Vi/Vc) transition and Vc/upper cervical cord (Vc/C1) regions. In addition, activated microglial cells were tightly wrapped around activated FOS neurons in both regions and phosphorylated p38 mitogen-activated protein kinase was markedly enhanced specifically in microglial cells during ocular inflammation. Similar data were obtained in the facial motor nucleus. These neuroanatomical data correlated with the increase in mRNA expression of pro-inflammatory (TNF-α, IL-6, CCL2) and neuronal (FOS and ATF3) markers. Interestingly, the suppression of corneal inflammation 10days following the end of BAC treatment resulted in a marked attenuation of peripheral and central changes observed in pathological conditions.This study provides the first demonstration that corneal inflammation induces activation of neurons and microglial p38 MAPK pathway within sensory trigeminal complex. These results suggest that this altered activity in intracellular signaling caused by ocular inflammation might play a priming role in the central sensitization of ocular related brainstem circuits, which represents a significant factor in ocular pain development.

Direct reticular projections of trigeminal sensory fibers immunoreactive to CGRP: potential monosynaptic somatoautonomic projections.

Few trigeminal sensory fibers project centrally beyond the trigeminal sensory complex, with only projections of fibers carried in its sensory anterior ethmoidal (AEN) and intraoral nerves described. Fibers of the AEN project into the brainstem reticular formation where immunoreactivity against substance P and CGRP are found. We investigated whether the source of these peptides could be from trigeminal ganglion neurons by performing unilateral rhizotomies of the trigeminal root and looking for absence of label. After an 8–14 days survival, substance P immunoreactivity in the trigeminal sensory complex was diminished, but we could not conclude that the sole source of this peptide in the lateral parabrachial area and lateral reticular formation arises from primary afferent fibers. Immunoreactivity to CGRP after rhizotomy however was greatly diminished in the trigeminal sensory complex, confirming the observations of others. Moreover, CGRP immunoreactivity was nearly eliminated in fibers in the lateral parabrachial area, the caudal ventrolateral medulla, both the peri-ambiguus and ventral parts of the rostral ventrolateral medulla, in the external formation of the nucleus ambiguus, and diminished in the caudal pressor area. The nearly complete elimination of CGRP in the lateral reticular formation after rhizotomy suggests this peptide is carried in primary afferent fibers. Moreover, the arborization of CGRP immunoreactive fibers in these areas mimics that of direct projections from the AEN. Since electrical stimulation of the AEN induces cardiorespiratory adjustments including an apnea, peripheral vasoconstriction, and bradycardia similar to those seen in the mammalian diving response, we suggest these perturbations of autonomic behavior are enhanced by direct somatic primary afferent projections to these reticular neurons. We believe this to be first description of potential direct somatoautonomic projections to brainstem neurons regulating autonomic activity.

Prednisolone induces microglial activation in the subnucleus caudalis of the rat trigeminal sensory complex.

Prednisolone is a member of synthetic glucocorticoids which are widely used to treat chronic inflammatory diseases. In this study, neuronal degeneration and cell death, and glial reaction were investigated in the rat trigeminal ganglion (TG) and brainstem after subcutaneous injection of prednisolone for 7 days. Expression of c-Jun activating transcription factor 3 and caspase-3 was absent or infrequent in the TG, and cranial sensory and motor nuclei of saline- and prednisolone-treated animals. In these animals, distribution of calcitonin gene-related peptide-immunoreactive (-IR) neurons and nerve fibers was similar in the brainstem. In addition, the number of Iba1- and glial fibrillary acidic protein (GFAP)-IR cells with some processes in the brainstem was barely affected by prednisolone treatment. However, the treatment increased ramification of Iba1-IR processes in the subnucleus caudalis of the trigeminal sensory complex. Prednisolone scarcely influenced the morphology of GFAP-IR cells in the brainstem. Expression of p38 mitogen-activated protein kinase was very rare in the brainstem of saline- and prednisolone-treated animals. The present study suggests that microglia are activated by prednisolone in the subnucleus caudalis of the trigeminal sensory complex. The glucocorticoid may affect nociceptive transmission in the brainstem.

Response properties of temporomandibular joint mechanosensitive neurons in the trigeminal sensory complex of the rabbit

The neurophysiological properties of neurons sensitive to TMJ movement (TMJ neurons) in the trigeminal sensory complex (Vcomp) during passive movement of the isolated condyle were examined in 46 rabbits. Discharges of TMJ neurons from the rostral part of the Vcomp were recorded with a microelectrode when the isolated condyle was moved manually and with a computer-regulated mechanostimulator. A total of 443 neurons responding to mechanical stimulation of the face and oral cavity were recorded from the brainstem. Twenty-one TMJ neurons were detected rostrocaudally from the dorsal part of the trigeminal principal sensory nucleus (NVsnpr), subnucleus oralis of the trigeminal spinal nucleus, and reticular formation surrounding the trigeminal motor nucleus. Most of the TMJ neurons were located in the dorso-rostral part of the NVsnpr. Of the TMJ units recorded, 90 % were slowly adapting and 26 % had an accompanying resting discharge. The majority (86 %) of the TMJ units responded to the movement of the isolated condyle in the anterior and/or ventral directions, and half were sensitive to the condyle movement in a single direction. The discharge frequencies of TMJ units increased as the condyle displacement and constant velocity (5 mm/s) increased within a 5-mm anterior displacement of the isolated condyle. Based on these results, we conclude that sensory information is processed by TMJ neurons encoding at least joint position and displacement in the physiological range of mandibular displacement.

Differential activation of mitogen-activated protein kinases and glial cells in the trigeminal sensory nuclear complex following lingual nerve injury

Differential activation of mitogen-activated protein kinases and glial cells in the trigeminal sensory nuclear complex following lingual nerve injury

The Role of Sensory Fiber Demography in Trigeminal and Postherpetic Neuralgias

In this study, we systematically investigated fiber demography, based on function and distribution, from the periphery to their destinations in the various central (sub) nuclei in the trigeminal brainstem nuclear sensory complex. Conventional and novel compelling information is provided, demonstrating that the ratio and somatotopy of types A and C sensory fibers at the site of a lesion can elucidate important puzzles in TNP disorders. For instance, we explain how of a major shift in the fibers’ direction and ratio at the level of the trigeminal root entry zone (REZ) influences the pathophysiology of pre- and typical trigeminal neuralgia. As a result, there is a high A/C ratio of oral and peri-oral fibers in the supero-medial region of the REZ, which is mostly susceptible to vascular compression. However, this A/C ratio varies considerably at lower proportions in other areas along the peripheral trigeminal pathway, where an injury (viral, vessel compression, or trauma) can lead to a broader spectrum of fiber involvement and, consequently, pain outcome. In summary, we explain how fiber demography can influence pain quality, location, temporal features, progress, and treatment prognosis of TNP in those patients who develop it.

Tonic and phasic descending dopaminergic controls of nociceptive transmission in the medullary dorsal horn

The transfer of nociceptive information at the level of dorsal horn is subject to extensive processing by both local segmental and supraspinal mechanisms, including descending dopaminergic controls, originating from the hypothalamic A11 nucleus. The inhibitory role of dopamine on evoked pain via activation of D2-like receptors at the level of the dorsal horn is well established. Here, by use of behavioral, electrophysiological, and anatomical techniques, we examined within the trigeminal sensory complex, first, whether descending dopaminergic controls also modulate pain behavior after an inflammatory insult, and second, under which physiological conditions these descending dopaminergic controls are actually recruited. We show that D2 receptors are mostly located within superficial medullary dorsal horn where trigeminal nociceptive fibers abut. Activating these D2-like receptors inhibits, whereas blocking them enhances, both formalin- and capsaicin-evoked pain behavior and C-fiber-evoked action potential firing of trigeminal wide dynamic range (WDR) neurons. Moreover, windup and diffuse noxious inhibitory controls (DNIC), 2 dynamic properties of C-fiber-evoked firing of WDR neurons, are inhibited by activating and blocking, respectively, these D2-like receptors. Altogether, our results are consistent with a tonic inhibition of the trigeminal nociceptive input by descending dopaminergic controls via activation of D2-like receptors at the level of superficial medullary dorsal horn. Such dopamine-dependent tonic inhibition of nociceptive information can be dynamically modulated by pain. This suggests that dysregulation of descending dopaminergic controls should translate in patients into diffuse, cephalic, and extracephalic pain symptoms—spontaneous pain, decreased pain thresholds, deficient DNIC, or some combination of these.Descending dopaminergic controls exert a tonic inhibition of trigeminal nociceptive information via D2-like receptors within superficial medullary dorsal horn. Dopamine-dependent tonic inhibition is dynamically modulated by pain.

Single unit oscillations in rat trigeminal nuclei and their control by the sensorimotor cortex

Oscillatory activity at both the single and multiunit levels has been reported in most central nervous system structures, and is postulated as a key factor in information processing and coding. Rats provide an excellent model for oscillation-based information processing, since tactile perception of the environment is achieved by rhythmic movements of their whiskers and information-related rhythmic activity has been identified in the thalamus and cortex. However, rhythmic activity related to information processing has never been reported in the sensory trigeminal complex (STC), the first brain stem relay station for whisker-related tactile information. In the present work, we demonstrate the existence of neural oscillations in the vibrissae-related neurons of the nuclei principalis (Pr5), oralis (Sp5o), interpolaris (Sp5i) and caudalis (Sp5c). Rhythmic activity was associated with the main task of each nucleus, prominent in nuclei responsible for tactile vibrissae information processing (up to 17% oscillating neurons in Pr5 and 26% in Sp5i) and less conspicuous in those concerned with pain (8% oscillating neurons in Sp5o and in Sp5c). The higher percentage of oscillating neurons and higher frequencies in Sp5i than in Pr5 suggests an active role for rhythmic activity in integrating multivibrissa inputs. Oscillations are generated within the brainstem; data obtained from decorticated animals suggest the existence of a differential cortical control of the rhythmic processes in STC nuclei. Corticofugal activity modifies oscillation frequency and synchronization strength of the rhythmic activity mainly during tactile stimulation of the vibrissae.

Long Lasting Pain Hypersensitivity following Ligation of the Tendon of the Masseter Muscle in Rats: A Model of Myogenic Orofacial Pain

BackgroundA major subgroup of patients with temporomandibular joint (TMJ) disorders have masticatory muscle hypersensitivity. To study myofacial temporomandibular pain, a number of preclinical models have been developed to induce myogenic pain of the masseter muscle, one of the four muscles involved in mastication. The currently used models, however, generate pain that decreases over time and only lasts from hours to weeks and hence are not suitable for studying chronicity of the myogenic pain in TMJ disorders. Here we report a model of constant myogenic orofacial pain that lasts for months.ResultsThe model involves unilateral ligation of the tendon of the anterior superficial part of the rat masseter muscle (TASM). The ligation of the TASM was achieved with two chromic gut (4.0) ligatures via an intraoral approach. Nocifensive behavior of the rat was assessed by probing the skin site above the TASM with a series of von Frey filaments. The response frequencies were determined and an EF50 value, defined as the von Frey filament force that produces a 50% response frequency, was derived and used as a measure of mechanical sensitivity. Following TASM ligation, the EF50 of the injured side was significantly reduced and maintained throughout the 8-week observation period, suggesting the presence of mechanical hyperalgesia/allodynia. In sham-operated rats, the EF50 of the injured side was transiently reduced for about a week, likely due to injury produced by the surgery. Somatotopically relevant Fos protein expression was indentified in the subnucleus caudalis of the spinal trigeminal sensory complex. In the same region, persistent upregulation of NMDA receptor NR1 phosphorylation and protein expression and increased expression of glial markers glial fibrillary acidic protein (astroglia) and CD11b (microglia) were found. Morphine (0.4-8 mg/kg, s.c.) and duloxetine (0.4-20 mg/kg, i.p.), a selective serotonin-norepinephrine reuptake inhibitor, produced dose-dependent attenuation of hyperalgesia.ConclusionsLigation injury of the TASM in rats led to long-lasting and constant mechanical hypersensitivity of myogenic origin. The model will be particularly useful in studying the chronicity of myogenic pain TMJ disorders. The model can also be adapted to other regions of the body for studying pathology of painful tendinopathy seen in sports injury, muscle overuse, and rheumatoid arthritis.