Blunted Behavioral and C Fos Responses to Acidic Fumes in the African Naked Mole-Rat

Acidosis in the skin triggers activation of pain pathways and behaviors indicative of pain in vertebrates. The exception is the naked mole-rat, the only known vertebrate to show physiological and behavioral insensitivity to acid pain in the skin. The goal of the present study was to determine behavioral and physiological responses of this species to airborne acidic fumes, which would be expected to affect the trigeminal pain pathway in other species. Behaviorally, naked mole-rats did not avoid fumes from moderately high concentrations of acetic acid (10 and 20%), and c Fos labeling showed no increase in activity in the trigeminal nuclei and nucleus tractus solitarius. In contrast, these concentrations triggered behavioral aversion and increased Fos activity in other laboratory rodents. For a very high concentration of acetic acid (50%), naked mole-rats showed significant avoidance behavior and increased Fos labeling in the nucleus tractus solitarius caudal region, which receives vagal chemosensory information. However, there was no increase in trigeminal labeling, and in fact, activity significantly decreased. This pattern is opposite of that associated with another irritant, ammonia fumes, which elicited an increase in trigeminal but not nucleus tractus solitarius Fos labeling, and no behavioral avoidance. Behavioral avoidance of acidic fumes, but no increased labeling in the trigeminal pain nucleus is consistent with the notion of adaptations to blunt acid pain, which would be advantageous for naked mole-rats as they normally live under chronically high levels of acidosis-inducing CO₂.     

Five-and-a-half years' experience with percutaneous retrogasserian glycerol rhizotomy in treatment of trigeminal neuralgia

The results of treating trigeminal neuralgia with percutaneous retroganglionic glycerol rhizotomy in 319 patients from an overall series of 394 patients with 459 operations carried out over a period of 5 1/2 years are reported. Idiopathic trigeminal neuralgia was the diagnosis in 252 patients. 34 patients had trigeminal neuralgia associated with multiple sclerosis. The remaining 33 patients suffered from symptomatic trigeminal neuralgia or atypical facial pain. 230 patients (91.3%) with idiopathic trigeminal neuralgia and 30 patients (88.2%) with multiple sclerosis reported complete freedom from pain. In 12 patients (4.8%) of those with tic douloureux and in 1 patient (2.9%) with multiple sclerosis, pain was alleviated, and the patients required a reduced pharmacotherapy. 10 patients (3.9%) and 3 patients (8.8%) were considered to be treatment failures. The rate of recurrences within the first 2 years was 10.9 and 40.0%, respectively. In the long-term, the rate of recurrences in patients with tic douloureux was 36.9%. 144 patients (45.1%) noticed a hypesthesia. 132 patients (41.4%) had hypalgesia following the procedure, and there was a decrease of symptoms in the long-term observation in 20.0% of the patients. 59 patients (18.5%) developed dysesthesia postoperatively which regressed only to an inappreciable extent in the long-term course. In 16 patients (5.0%) exclusively with a preexisting organic lesion or who had received surgical pretreatment, there was a loss of corneal sensation. The investigation showed on the one hand the effectiveness of the method, but on the other hand also the possibility of marked sensory disorder in selected cases.     

A method for bulbospinal trigeminal nucleotomy in the treatment of facial deafferentation pain

Many types of facial pain are difficult to treat, such as postherpetic, posttraumatic, or pain following denervation procedures used in the treatment of trigeminal neuralgia (anesthesia dolorosa), all of which involve deafferentation of the spinal trigeminal nucleus.     

Extreme tolerance to ammonia fumes in African naked mole-rats: animals that naturally lack neuropeptides from trigeminal chemosensory nerve fibers

Naked mole-rats (Heterocephalus glaber) naturally lack neuropeptides associated with the signaling of chemical irritants from C type trigeminal nerve fibers. The goal of the present study was to assess behavioral responses of these animals to stimulation of the trigeminal chemosensory system, and to determine if stimulation would increase post-synaptic activity in the trigeminal nucleus, as seen in laboratory mice and rats. The results show that naked mole-rats are behaviorally insensitive to capsaicin solution applied to the nostrils and to ammonia fumes in a behavioral avoidance test. Centrally, the number of c Fos labeled cells in the spinal trigeminal nucleus increased from exposure to ammonia although the magnitude of the increase was less than for rats. The increase observed in naked mole-rats likely reflects activity from glutamate release, which appears insufficient to drive pain and aversion behaviors. The results support the idea that neuropeptides in the C fibers of the trigeminal system may be required to signal the aversive quality of specific chemical irritants. The natural lack of neuropeptides in naked mole-rats may be an adaptation to living in a challenging subterranean environment with extremely high levels of ammonia and carbon dioxide, stimuli known to excite trigeminal chemosensory C fibers.     

两种非甾体类抗炎药对清醒状态血管源性头痛模型大鼠颅内Fos表达的影响

目的通过观察血管源性头痛清醒动物模型中Fos阳性细胞在三叉神经节及三叉神经脊束核尾侧亚核的分布情况,明确两种非甾体类抗炎药NSAID对乙酰氨基酚及布洛芬在头痛控制中,在颅内特定区域的作用机理。方法 30只雄性SD大鼠随机分为对照组(生理盐水组)、对乙酰氨基酚组、布洛芬组,每组给药后50 min分别给予频率为20 Hz、电流为3~5 mA和脉宽为0.25 ms的电刺激,刺激后给予大鼠灌注固定取脑,分别在颅内取三叉神经节及三叉神经脊束核尾侧亚核制作石蜡切片,进行免疫组织化学染色,利用Image J软件对阳性细胞进行计数统计。结果电刺激后盐水组与非甾体类药物组在双侧三叉神经节、三叉神经脊束核尾侧亚核Fos蛋白表达的差异具有显著统计学意义,对乙酰氨基酚组与布洛芬组在双侧三叉神经节、三叉神经脊束核尾侧亚核Fos蛋白表达未见统计学差异。结论给予非甾体类抗炎前后在双侧三叉神经节、三叉神经脊束核尾侧亚核的Fos表达的改变提示三叉神经节、三叉神经脊束核尾侧亚核参与了疼痛的传递和表达以及药物对疼痛控制的药理过程。     

Epileptiform activity in the somatosensory cortex of rats with trigeminal neuralgia]

It was shown in experiments on rats that penicillin 1 microliter microinjection (100 U) into the caudal nucleus of the spinal tract of the trigeminal nerve, accounting for formation of a generator of pathologically enhanced excitation (GREE), brings about in rats the pain syndrome with characteristic for trigeminal neuralgia behavioural manifestations and the emergence of epileptiform activity in the somatosensory cortex, especially pronounced in the contralateral hemisphere. The emergence of this activity reflects, on the one hand, the action of the GREE in the caudal nucleus of the trigeminal nerve and, on the other hand, the involvement of the somatosensory cortex taking over stimulation from the hyperactive caudal nucleus, into formation of a pathological algic system of this form of trigeminal neuralgia.     

Gamma-aminobutyric acid-immunoreactive neurons in the rat trigeminal nuclei

The distribution of GABAergic neurons in the rat trigeminal nuclei was studied using a highly specific monoclonal antibody (mAb3A12) to gamma-aminobutyric acid (GABA). Immunopositive cells were relatively abundant in the marginal and gelatinosa beds of the caudal part of the trigeminal spinal tract nucleus, and in the dorsomedial areas of the oral subnucleus and the principal nucleus. A high density of GABA-immunoreactive somata was also found in the rostral part of the oral subnucleus and in the adjacent parvicellular reticular formation as well as in the supratrigeminal and intertrigeminal regions. Thus, the distribution of the GABAergic cells showed a relatively high density in areas related to the convergence of sensory stimuli, and in zones that contain interneurons inhibiting masticatory motorneurons. The results suggest, therefore, that GABA might play an important role both in discriminative sensory processing and in reflex modulation of the orofacial region.Abbreviations RF reticular formation - FRp parvicellular reticular formation - Vc trigeminal nucleus of the spinal tract, subnucleus caudalis - Vmes mesencephalic nucleus - Vmo trigeminal motor nucleus - Vo trigeminal nucleus of the spinal tract, subnucleus oralis - Vp principal trigeminal nucleus - Vsp spinal trigeminal nucleus - Vsup supratrigeminal nucleus     

Lesions of spinal and trigeminal dorsal root entry zone for deafferentation pain. Experience of 35 cases

Spinal and trigeminal dorsal root entry zone destruction (DREZ-tomy) was performed on 35 patients with deafferentation pain of various types. Overall, satisfactory pain relief was obtained in 65.5% of spinal DREZ-tomy cases in the follow-up observation. The result in the brachial plexus avulsion group was the best (82.4% improved), followed by the limb pain group without root avulsion (50.0%), but the truncal or visceral pain group showed the worst result (33.3%). Two patients with postherpetic trigeminal neuralgia were completely relieved of pain in the average follow-up period of 32 months, while in 2 patients with postrhizotomy facial pain, pain recurred 4 months after the operation in 1, and, in the other, pain in the medial part of the face remained unchanged. Complications were seen in about 60% of the patients, which were, however, all mild, except for 2 cases of death due to gastrointestinal disease.     

Functional imaging of the human trigeminal system: opportunities for new insights into pain processing in health and disease

Peripheral inflammation or nerve damage result in changes in nervous system function, and may be a source of chronic pain. A number of animal studies have indicated that central neural plasticity, including sensitization of neurons within the spinal cord and brain, is part of the response to nervous system insult, and can result in the appearance of altered sensation, including pain. It cannot be assumed, however, that data obtained from animal models unambiguously reflects CNS changes that occur in humans. Currently, the only noninvasive approach to determining objective changes in neural processing and responsiveness within the CNS in humans is the use of functional imaging techniques. It is now possible to use functional magnetic resonance imaging (fMRI) to measure CNS activation in the trigeminal ganglion, spinal trigeminal nucleus, the thalamus, and the somatosensory cortex in healthy volunteers, in a surrogate model of hyperalgesia, and in patients with trigeminal pain. By offering a window into the temporal and functional changes that occur in the damaged nervous system in humans, fMRI can provide both insight into the mechanisms of normal and pathological pain and, potentially, an objective method for measuring altered sensation. These advances are likely to contribute greatly to the diagnosis and treatment of clinical pain conditions affecting the trigeminal system (e.g., neuropathic pain, migraine).     

Deafferentation pain and stimulation of the thalamic sensory relay nucleus: clinical and experimental study

This report summarizes our clinical experience in which the effects of both thalamic sensory relay nucleus (TSRN) and periaqueductal gray (PAG) stimulation were tested in the same series of patients with various forms of pain. The clinical data indicated that neurogenic pain due to deafferentation at the level of the peripheral nerves or the spinal cord was often controlled by TSRN stimulation but not by PAG stimulation. We also review the results of our experimental investigations in cats which were undertaken in an attempt to clarify the neurophysiologic basis of such differential clinical effects of TSRN and PAG stimulation. It appeared that abnormal hyperactivity within the trigeminal medullary dorsal horn following retrogasserian rhizotomy was far more frequently inhibited by TSRN stimulation than by PAG stimulation.     

The interstitial system of the trigeminal spinal tract projects to the red nucleus in mice

We studied projections from the interstitial system of the spinal trigeminal tract (InSy-S5T) to the red nucleus of the mouse with retrograde tracers (fluorogold and latex microbeads impregnated with rhodamine and fluorescein). Injections in the magnocellular part of the red nucleus caused labeling of cells in the rostral, intermediate, and caudal paratrigeminal nucleus (Pa5), dorsal paramarginal nucleus (PaMD), insular trigemeo-lateral cuneate nucleus (I5CuL), and the trigeminal extension of the parvocellular reticular formation (5RPC). All projections were bilateral, but contralateral projections were stronger. The number of retrogradely labeled cells in the InSy-S5T in 3-, 6-, and 12-month-old mice was similar. Injections restricted to the parvocellular red nucleus did not label the nuclei of the InSy-S5T. This projection from the InSy-S5T to the red nucleus may mediate modulation of the facial muscles by pain and other sensory information.     

CT引导下立体定向射频热凝三叉神经半月节对原发性三叉神经痛的疗效分析

目的：分析CT引导下立体定向射频热凝三叉神经半月节对原发性三叉神经痛的疗效,探讨其临床适用性。方法：选择从2011年5月至2012年12月于我院住院治疗原发性三叉神经痛的58例患者,在三维CT引导下采用通过BrainLAB手术计划系统经前入路卵圆孔穿刺三叉神经半月神经节,术中根据疼痛分布范围射频热凝三叉神经半月节。观察并比较治疗前后的VAS评分,临床疗效,术中和术后不良反应情况。结果：58例患者的穿刺手术均成功,术后1d、3d、6d的VAS评分均较治疗前显著降低（P〈0．01）;1周后58例患者中,有53例患者疼痛完全消失,l例患者偶然出现疼痛,但无需服用药物处理,共显效54例;4例患者疼痛有所减轻或疼痛发作频率降低,但仍需服用药物,或服用药物剂量较治疗前明显减少;疼痛无改善或者非用药不能缓解的持续痛仅1例。总有效例数为57例,总有效率达98．26％。术中发生不良反应6例,在术后均有所缓解。术后发生各种并发症共15例,均未明显影响手术效果。结论：CT引导可以较为准确的进入穿刺部位,使立体定向射频热凝三叉神经半月节手术更加顺利,达到治疗原发性三叉神经痛的理想效果,适合临床长期推广应用。     

The interstitial system of the trigeminal spinal tract projects to the red nucleus in mice

We studied projections from the interstitial system of the spinal trigeminal tract (InSy-S5T) to the red nucleus of the mouse with retrograde tracers (fluorogold and latex microbeads impregnated with rhodamine and fluorescein). Injections in the magnocellular part of the red nucleus caused labeling of cells in the rostral, intermediate, and caudal paratrigeminal nucleus (Pa5), dorsal paramarginal nucleus (PaMD), insular trigemeo-lateral cuneate nucleus (I5CuL), and the trigeminal extension of the parvocellular reticular formation (5RPC). All projections were bilateral, but contralateral projections were stronger. The number of retrogradely labeled cells in the InSy-S5T in 3-, 6-, and 12-month-old mice was similar. Injections restricted to the parvocellular red nucleus did not label the nuclei of the InSy-S5T. This projection from the InSy-S5T to the red nucleus may mediate modulation of the facial muscles by pain and other sensory information.     

Electrical stimulation of the trigeminal tract in chronic, intractable facial neuralgia

In this paper the treatment of patients with chronic, intractable trigeminal neuralgia by invasive electrical stimulation of the Gasserion ganglion is reviewed. Two different surgical techniques are employed in this treatment. Most frequently, a method similar to the traditional technique for percutaneous glycerol and radiofrequency trigeminal rhizolysis is used: a small percutaneous stimulation electrode is advanced under fluoroscopic control through a thin needle via the foramen ovale to the Gasserian cistern. Some neurosurgeons use an open surgical technique by which the Gasserian ganglion is approached subtemporally and extradurally, and the bipolar pad electrode is sutured to the dura. When percutaneous test stimulation is successful (at least 50% pain relief) the electrode is internalized and connected to a subcutaneous pulse generator or RF-receiver. Data from 8 clinical studies, including 267 patients have been reviewed. Of all 233 patients with medication-resistant atypical trigeminal neuralgia 48% had at least 50% long term pain relief. The result of test stimulation is a good predictor of the long term effect, because 83% of all patients with successful test stimulation had at least 50% long term relief, and 70% had at least 75% long term relief. Patients generally preferred this invasive method over TENS. The success rate in patients with postherpetic trigeminal neuralgia was very low (less than 10%). It is suggested that the likelihood of pain relief by electrical stimulation is inversely related to the degree of sensory loss. It is concluded that invasive stimulation of the Gasserian ganglion is a promising treatment modality for patients with chronic, intractable, atypical trigeminal neuralgia.     

Trigeminal neuralgia: a retrospective study of 188 Thai cases

doi: 10.1111/j.1741‐2358.2011.00530.x Trigeminal neuralgia: a retrospective study of 188 Thai cases Objective: To describe the clinical characteristics and treatment of trigeminal neuralgia (TN) in a group of Thai patients. Materials and methods: Records of 188 patients with TN were reviewed retrospectively for patient demographics, the characteristics of the pain and treatment modalities. Results: Of the 188 patients, 37.2% were men and 62.8% were women. The peak incidence (46.8%) was in the age range of 50–69 years. Pain occurred on the right side of the face more often than on the left (1.8:1). The mandibular division of the trigeminal nerve was the most frequently affected (30.3%), followed by the combined maxillary and mandibular divisions (29.3%) and the maxillary division alone (25%). The majority described their attack as a sharp pain (77.6%), and the most common primary locations were at previous extraction sites (40.5%). The most common triggers were chewing (61.2%) and speaking (47.3%). Carbamazepine was the most common prescribed drug (76.1%) for the initial treatment. Combination drug therapy was introduced when the monotherapy failed to control the pain. Surgical intervention was the alternative choice of treatment in refractory cases. Conclusion: TN affected women more than men, and this disorder occurred most frequently in patients aged 50 years and older. The mandibular division of the trigeminal nerve was most commonly involved.     

Percutaneous Radio-Frequency Rhizotomy in the Treatment of Trigeminal Neuralgia

A percutaneous technique of selective partial trigeminal root coagulation was evaluated in the treatment of 38 patients suffering from trigeminal neuralgia, 1 patient with pain secondary to oral carcinoma and 1 patient with atypical facial pain. The pain of trigeminal neuralgia was relieved in 94.7 percent of patients. Pain was relieved in the patient with oral carcinoma, but not in the patient with atypical facial pain. There was no mortality and no permanent morbidity outside of the trigeminal nerve lesion. The procedure requires only a brief hospital stay without the time, expense and hazards of open cranial surgical procedures.     

Arrangement and connections of mesencephalic trigeminal neurons in the rat

The morphology of the mesencephalic trigeminal nucleus was examined microscopically in serial frozen sections. The nucleus extends over a length of about 4.5 mm, and its cell number was calculated to range from 1,000 to 1,600. 60% of the cells were located in the caudal third of the nucleus. Clustering of large unipolar cells was seen throughout the nucleus. Small spindle-shaped multipolar cells were found in the pontine part of the nucleus. The efferent connections of the mesencephalic trigeminal neurons were investigated by means of iontophoretically delivered Phaseolus vulgaris leuco-agglutinin or horseradish peroxidase after electrophysiological identification of mesencephalic trigeminal neurons. All projections were found ipsilateral to the injection site; they were confined to the trigeminal motor nucleus, especially to its lateral part, and to the dorsolateral reticular formation. The latter projection area included the supratrigeminal nucleus, the nucleus of Probst, and the parvocellular reticular zone. There were no direct projections to the facial or hypoglossal motor nuclei. It is concluded that proprioceptive input from one side is mediated polysynaptically to the bilateral oral final common-path neurons, with the exception of the ipsilateral trigeminal motoneurons.     

Calcitonin gene-related peptide enhances release of native brain-derived neurotrophic factor from trigeminal ganglion neurons

Activity-dependent plasticity in nociceptive pathways has been implicated in pathomechanisms of chronic pain syndromes. Calcitonin gene-related peptide (CGRP), which is expressed by trigeminal nociceptors, has recently been identified as a key player in the mechanism of migraine headaches. Here we show that CGRP is coexpressed with brain-derived neurotrophic factor (BDNF) in a large subset of adult rat trigeminal ganglion neurons in vivo. Using ELISA in situ, we show that CGRP (1-1000 nM) potently enhances BDNF release from cultured trigeminal neurons. The effect of CGRP is dose-dependent and abolished by pretreatment with CGRP receptor antagonist, CGRP(8-37). Intriguingly, CGRP-mediated BDNF release, unlike BDNF release evoked by physiological patterns of electrical stimulation, is independent of extracellular calcium. Depletion of intracellular calcium stores with thapsigargin blocks the CGRP-mediated BDNF release. Using transmission electron microscopy, our study also shows that BDNF-immunoreactivity is present in dense core vesicles of unmyelinated axons and axon terminals in the subnucleus caudalis of the spinal trigeminal nucleus, the primary central target of trigeminal nociceptors. Together, these results reveal a previously unknown role for CGRP in regulating BDNF availability, and point to BDNF as a candidate mediator of trigeminal nociceptive plasticity.     

Central mechanisms of vascular headaches

The intracranial blood vessels supplying the dura and brain are innervated by sensory afferents from the trigeminal nerve. These fibers are believed to be responsible for conveying the pain associated with vascular head pain such as migraines. This paper reviews recently published data describing the existence of neurons within the cat trigeminal nucleus and thalamus that respond to electrical stimulation of the middle meningeal artery and superior sagittal sinus. Almost all of these neurons receive convergent input from the facial skin and most of the receptive fields include the periorbital region. On the basis of their cutaneous inputs, most of the neurons are classified as nociceptive. The characteristics of these cerebrovascular-activated neurons are consistent with their role in mediating vascular head pains and with the typical referral of such pains in man to the orbital region. This paper also presents preliminary results of recordings from rat trigeminal ganglion neurons activated by electrical stimulation of the middle meningeal artery and sagittal sinus. The latencies of activation of these neurons are indicative of conduction in slowly conducting myelinated axons and in unmyelinated axons. Some of the neurons could also be activated by mechanical stimuli applied to the vessels.     

Morphological alteration in oro-facial CGRP containing motoneurons due to congenital thyroid hypofunction

Under congenital thyroid hypofunction, the oro-facial large and small calcitonin gene-related peptide (CGRP) immunoreactive motoneurons were classified into strong, moderate, weak and negative intensity in offspring weaned rats. While 50% of neurons in the trigeminal motor nucleus (Mo5) were of the large type, this value dropped to 30% in hypothyroid pups. Hypothyroid trigeminal accessory nucleus (Mo5-AC) contained 10% large motoneurons versus about 45% in normal pups. Normal facial nucleus (Mo7) had 20% large motoneurons in contrast with 10% in hypothyroid pups. These values are significant in comparison with the normal pattern of oro-facial CGRP positive immunoreactive motoneurons as well as those devoid of immunostaining.