Stimulating GABAergic Neurons in the Nucleus Accumbens Core Alters the Trigeminal Neuropathic Pain Responses in a Rat Model of Infraorbital Nerve Injury.

The nucleus accumbens core (NAcc) is an important component of brain reward circuitry, but studies have revealed its involvement in pain circuitry also. However, its effect on trigeminal neuralgia (TN) and the mechanism underlying it are yet to be fully understood. Therefore, this study aimed to examine the outcomes of optogenetic stimulation of NAcc GABAergic neurons in an animal model of TN. Animals were allocated into TN, sham, and control groups. TN was generated by infraorbital nerve constriction and the optogenetic virus was injected into the NAcc. In vivo extracellular recordings were acquired from the ventral posteromedial nucleus of the thalamus. Alterations of behavioral responses during stimulation "ON" and "OFF" conditions were evaluated. In vivo microdialysis was performed in the NAcc of TN and sham animals. During optogenetic stimulation, electrophysiological recordings revealed a reduction of both tonic and burst firing activity in TN animals, and significantly improved behavioral responses were observed as well. Microdialysis coupled with liquid chromatography/tandem mass spectrometry analysis revealed significant alterations in extracellular concentration levels of GABA, glutamate, acetylcholine, dopamine, and citrulline in NAcc upon optic stimulation. In fine, our results suggested that NAcc stimulation could modulate the transmission of trigeminal pain signals in the TN animal model.

Cognitive and sensorimotor function in participants being treated for trigeminal neuralgia pain.

BACKGROUND: Trigeminal neuralgia (TN) is an orofacial condition defined by reoccurring, spontaneous, short-lived but excruciating stabbing pain. Pharmacological interventions constitute the first-line treatment for TN, with antiepileptic drugs commonly prescribed. People treated for TN pain with antiepileptic drugs describe cognitive and motor difficulties affecting activities of daily living, and report poorer quality of life. We undertook the first comprehensive objective evaluation of sensorimotor and cognitive performance in participants being treated for TN pain with antiepileptic drugs relative to age-matched controls. METHODS: Participants (43 TN, 41 control) completed a battery of sensorimotor (steering, aiming and tracking) and cognitive (working memory, processing speed, inhibition) tasks. RESULTS: The TN group performed significantly worse than controls on the sensorimotor tracking and aiming tasks and across all cognitive measures. CONCLUSIONS: The data explain why patients treated with antiepileptic drugs report impairment when conducting activities of daily living (given the need for cognitive and motor capability within most of these). The study is an important first step in: (i) ensuring there is adequate information on the impact of pharmacological treatment; (ii) identifying measures to determine optimal medication dosage and track change over time; (iii) creating an evidence base that could allow scientific justification of alternative pain treatment options for TN (e.g. the costs/benefits of surgery).

Motor cortex stimulation in chronic neuropathic orofacial pain syndromes: a systematic review and meta-analysis.

Invasive motor Cortex Stimulation (iMCS) was introduced in the 1990's for the treatment of chronic neuropathic orofacial pain (CNOP), although its effectiveness remains doubtful. However, CNOP is known to be a heterogeneous group of orofacial pain disorders, which can lead to different responses to iMCS. Therefore, this paper investigated (1) whether the effectiveness of iMCS is significantly different among different CNOP disorders and (2) whether other confounding factors can be impacting iMCS results in CNOP. A systematic review and meta-analysis using a linear mixed-model was performed. Twenty-three papers were included, totaling 140 CNOP patients. Heterogeneity of the studies showed to be 55.8%. A visual analogue scale (VAS) measured median pain relief of 66.5% (ranging from 0-100%) was found. Linear mixed-model analysis showed that patients suffering from trigeminal neuralgia responded significantly more favorable to iMCS than patients suffering from dysfunctional pain syndromes (p = 0.030). Also, patients suffering from CNOP caused by (supra)nuclear lesions responded marginally significantly better to iMCS than patients suffering from CNOP due to trigeminal nerve lesions (p = 0.049). No other confounding factors were elucidated. This meta-analysis showed that patients suffering from trigeminal neuralgia and patients suffering from (supra)nuclear lesions causing CNOP responded significantly more favorable than others on iMCS. No other confounding factors were found relevant.

Effects of palmatine on BDNF/TrkB-mediated trigeminal neuralgia.

Trigeminal neuralgia (TN), a sudden, needle-like pain in the distribution area of the trigeminal nerve, can seriously affect the physical and mental health of patients. In chronic pain conditions including TN, increased levels of brain-derived neurotrophic factor (BDNF) may enhance pain transmission. This study compares the effect of palmatine administration on the expression of BDNF and its receptor TrkB (tropomyosin receptor kinase B) in trigeminal ganglion cells of Sprague-Dawley rats in a sham versus TN model group. Within 14 days of surgery, the mechanical allodynia threshold of the TN group was significantly lower than that of the sham group, while the TN + palmatine group had a higher mechanical pain sensitivity threshold than the TN group (p < 0.05). Real-time quantitative PCR, immunohistochemistry, and immunofluorescence showed that BDNF and TrkB expression in the TN group was higher than that in the sham group, while palmatine treatment could reverse these changes. Western blotting showed that palmatine treatment could reduce the elevated phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) in TN rats. Thus, the BDNF/TrkB pathway may be involved in the pain transmission process of TN, and palmatine treatment may reduce pain transmission by inhibiting the BDNF/TrkB pathway and suppressing ERK1/2 phosphorylation.

[New data for the pathomechanism of neuropathic pain: therapeutic evidences]. / Új adatok a neuropátiás fájdalom patomechanizmusához: terápiás evidenciák.

The present work is based on literature data from PubMed. Neuropathic pain is caused by a lesion or disease of the somatosensory system. Peripheral and central sensitization play a crucial role in its pathomechanism. The clinical symptoms are mainly characterized by burning and throbbing pain and sensory disturbances like hyperalgesia and allodynia. Therapeutic recommendations are antidepressants, antiepileptics, opioids and neuro-stimulation methods.

[Clinical efficacy observation on primary trigeminal neuralgia treated with joint needling method at the trigger point].

OBJECTIVE: To observe the clinical efficacy on primary trigeminal neuralgia treated with joint needling method at the trigger point. METHODS: One hundred and three cases of primary trigeminal neuralgia were divided into a joint needling group (53 cases) and a conventional needling group (50 cases) according to the visit sequence. In the joint needling group, the joint needling method was used at the trigger point in the mandibular joint [the positive point near to Xiaguan (ST 7)]; the conventional needling was used at Hegu (LI 4), Waiguan (TE 5), Taichong (LR 3) and Neiting (ST 44). In the conventional needling group, Xiaguan (ST 7) and Fengchi (GB 20) were used and the supplementary acupoints were selected according to the involved branches of trigeminal nerve. The conventional needling method was used. The Visual Analogue Scale (VAS) and the score of trigeminal neuralgia were adopted to assess the pain severity and the comprehensive symptoms before treatment and after the 1st and 2nd sessions of treatment separately. The efficacy was assessed. RESULTS: After the 1st and 2nd sessions of treatment, VAS score and the comprehensive symptom score were reduced obviously as compared with those before treatment in either group (P < 0.05, P < 0.01). The score reducing in the joint needling group was much superior to that in the conventional needling group (both P < 0.05). The total effective rate was 90.6% (48/53) and 72. 0% (36/50) in the joint needling group and the conventional needling group respectively. The effect in the joint needling group was better than that in the conventional needling group (P < 0.05). CONCLUSION: The joint needling method at the trigger point achieves the significant efficacy on primary trigeminal neuralgia, which is superior to that with the conventional needling method.

[Trigeminal neuralgia of hyperactive of liver yang type treated with acupuncture at Xiaguan (ST 7) at different depth: a randomized controlled trial].

OBJECTIVE: To observe the differences of therapeutic effect in primary trigeminal neuralgia (PTN) of hyperactive of liver yang type treated by deep and shallow puncturing at Xiaguan (ST 7). METHODS: Sixty-three cases of PTN of hyperactive of liver yang type were randomly divided into a deep puncturing group (32 cases) and a shallow puncturing group (31 cases). Xiaguan (ST 7) of affected region, Hegu (LI 4) and Taichong (LV 3) of bilateral sides, Cuanzhu (BL 2), Sibai (ST 2) and Jiachengjiang (Extra) relevant to the affected branch of nerve stem were selected in both groups. In deep puncturing group, Xiaguan (ST 7) was punctured to the depth of spheno-palatine ganglion (SPG); Cuanzhu (BL 2), Sibai (ST 2) and Jiachengjiang (Extra) were respectively punctured to the depth of supraorbital foramen, infraorbital foramen and mental foramen. In shallow group, routine puncturing was applied; the needles were connected with G6805 electric acupuncture apparatus, and switched on for 30 min every time; the treatment was applied every other day. Pain index, traditional Chinese medicine symptoms index and clinical therapeutic effect were observed after 2 courses of treatment. RESULTS: In deep puncturing group, the VAS scores and the traditional Chinese medicine symptoms scores (pain degree, pain frequency, upsetting, conjunctival congestion, bitter mouth and hypochondriac pain) after treatment were much more lower than those before treatment (all P < 0.01); in shallow puncturing group, except hypochondriac pain (P > 0.05), other indices above after treatment were obviously lower than those before treatment (P < 0.01, P < 0.05). Compared with the indices in both groups after treatment, the VAS scores, the pain degree, conjunctival congestion and total scores of traditional Chinese medicine symptoms in deep puncturing group were more significant (all P < 0.05). The total effective rate was 93.8% (30/32) in deep puncturing group, superior to that of 87.1% (27/31) in shallow puncturing group (P < 0.05). No any adverse reaction was observed in both groups. CONCLUSION: The therapeutic effect of trigeminal neuralgia of hyperactive of liver yang type treated with electroacupuncture is remarkable, and deep puncturing at Xiaguan(ST 7) to SPG is more effective than routine puncturing.

Intracranial neurostimulation for pain control: a review.

Intracranial neurostimulation for pain relief is most frequently delivered by stimulating the motor cortex, the sensory thalamus, or the periaqueductal and periventricular gray matter. The stimulation of these sites through MCS (motor cortex stimulation) and DBS (deep brain stimulation) has proven effective for treating a number of neuropathic and nociceptive pain states that are not responsive or amenable to other therapies or types of neurostimulation. Prospective randomized clinical trials to confirm the efficacy of these intracranial therapies have not been published. Intracranial neurostimulation is somewhat different than other forms of neurostimulation in that its current primary application is for the treatment of medically intractable movement disorders. However, the increasing use of intracranial neurostimulation for the treatment of chronic pain, especially for pain not responsive to other neuromodulation techniques, reflects the efficacy and relative safety of these intracranial procedures. First employed in 1954, intracranial neurostimulation represents one of the earliest uses of neurostimulation to treat chronic pain that is refractory to medical therapy. Currently, 2 kinds of intracranial neurostimulation are commonly used to control pain: motor cortex stimulation and deep brain stimulation. MCS has shown particular promise in the treatment of trigeminal neuropathic pain and central pain syndromes such as thalamic pain syndrome. DBS may be employed for a number of nociceptive and neuropathic pain states, including cluster headaches, chronic low back pain, failed back surgery syndrome, peripheral neuropathic pain, facial deafferentation pain, and pain that is secondary to brachial plexus avulsion. The unique lack of stimulation-induced perceptual experience with MCS makes MCS uniquely suited for blinded studies of its effectiveness. This article will review the scientific rationale, indications, surgical techniques, and outcomes of intracranial neuromodulation procedures for the treatment of chronic pain.

Bioresonance hypothesis: a new mechanism on the pathogenesis of trigeminal neuralgia.

Trigeminal neuralgia (TN) is an uncommon disorder characterized by recurrent attacks of lancinating pain in the trigeminal nerve distribution. To date, the precise mechanism for TN remains unclear. Among a variety of causes of TN, the microvascular compression (MVC) hypothesis is the most popular one, but controversies still focus on the origin and pathogenesis of the disorder. A number of clinical phenomena still cannot be well explained. We propose a new hypothesis on the pathogenesis of TN - bioresonance. The bioresonance hypothesis states that when the vibration frequency of a structure surrounding the trigeminal nerve becomes close to its natural frequency, the resonance of the trigeminal nerve occurs. The bioresonance can damage trigeminal nerve fibers and lead to the abnormal transmission of the impulse, which may finally result in facial pain. Under the guidance of the bioresonance hypothesis, we hope to explore more non-invasive methods to treat or even cure TN.

SUNCT syndrome successfully treated with the combination of oxcarbazepine and gabapentin.

Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) is a syndrome of intermittent, brief, unilateral, severe paroxysms of orbital-temporal pain recurring multiple times per day. The pain modulation is often very difficult. The reported SUNCT patient is the first who responded to a combination treatment of oxcarbazepine and gabapentin.

Trigeminal neuralgia: outcomes after gamma knife radiosurgery.

BACKGROUND: Trigeminal neuralgia (TN) often remains difficult to treat despite multiple available medications, and can severely impact on the quality of life of affected patients. Gamma knife radiosurgery has recently emerged as a minimally-invasive alternative to surgery for patients suffering from drug-resistant TN. The goal of this study was to report the short-term efficacy of gamma knife radiosurgery for TN and assess its impact on the quality of life of patients treated in the first 18 months of our experience. METHODS: Patients with medically-refractory TN or with unacceptable drug side effects were considered for radiosurgery. A maximum dose of 80 Gy was administered to the affected nerve using a single 4-mm isocenter. Follow-up assessments were made at 2,4 and 6 months, with evaluation of pain relief, drug reduction and quality of life. Factors impacting treatment response were assessed using Cox regression analysis. RESULTS: A total of 67 patients were treated. Significant pain relief was seen in 77.6% of patients, including 32.6% who became pain-free. Patients were able to discontinue all medications in 34.3% or reduce drug intake by more than 50% in an additional 28.4% of cases. No variable was found to predict pain relief although older age (>66 years) approached statistical significance. Sensory side effects were seen in 14.9% of patients. Quality of life improved in the majority of patients after radiosurgery. CONCLUSIONS: Gamma knife radiosurgery is a safe and effective management alternative for trigeminal neuralgia, providing good or excellent pain relief and improvement in quality of life in the majority of patients with few side effects.

A multiarray mapping method to minimize morbidity from thermocoagulation as treatment of refractory trigeminal neuralgia.

BACKGROUND: Conventional percutaneous thermocoagulation of postgasserian fibers has shown high success rates, with significant residual morbidity. METHODS: This communication summarizes conclusions of multiple publications on our computerized mapping method and technique, and presents new data on short- and long-term results on trigeminal pain, including an actuarial analysis, complications. RESULTS: In TTN, 97.4% of 75 procedures produced initial pain relief without medication. In all, 84.7% of appropriate verbal responses were achieved by proper location of the needle at the chosen target, requiring an average of 1.45 tracts per procedure. Needle tip was located between 1 and 15 mm below the sellar floor in 97.0% of procedures and in an angle of 40 degrees to 80 degrees regarding the clivus profile projection in 99.1%. A 93% reduction of corneal analgesia and a 100% suppression of major dysesthesias and cranial nerve palsies were found. CONCLUSION: We have shown a significant reduction of morbidity from percutaneous thermocoagulation of postgasserian fibers with similar short- and long-term results as those shown in 11 recently selected series. Strict adherence to all details of our new method and technique is essential. Future multiinstitutional studies are needed to confirm and enrich this small series.

Responsiveness of short-lasting unilateral neuralgiform headache with conjunctival injection and tearing to hypothalamic deep brain stimulation.

Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) is a severe primary headache disorder that is often refractory to medical therapy. Although the pathogenesis of this and other trigeminal autonomic cephalalgias is not completely understood, ipsilateral activation of the posterior and inferior hypothalamus has been identified on functional imaging studies during attacks. The authors report on a case of SUNCT syndrome successfully treated with hypothalamic deep brain stimulation and discuss the current literature.

Activation of interleukin-1beta receptor suppresses the voltage-gated potassium currents in the small-diameter trigeminal ganglion neurons following peripheral inflammation.

The glial cytokine, interleukin-1beta (IL-1beta), potentiates the excitability of nociceptive trigeminal ganglion (TRG) neurons via membrane depolarization following peripheral inflammation. Perforated patch-clamp technique was used this study to show that the mechanism underlying the excitability of small-diameter TRG neurons following inflammation is due to IL-1beta. Inflammation was induced by injection of complete Freund's adjuvant (CFA) into the whisker pad. The TRG neurons innervating the site of inflammation were identified by fluorogold (FG) labeling. The threshold for escape from mechanical stimulation applied to the orofacial area in inflamed rats was significantly lower than observed for control rats. IL-1beta at 1nM suppressed total voltage-gated K(+) currents in most TRG neurons (70%) under voltage-clamp conditions in control and inflamed rats. IL-1beta significantly decreased the total, transient (I(A)) and sustained (I(K)) currents in FG-labeled small-diameter TRG neurons in both groups. The IL-1beta-induced suppression of TRG neuron excitability was abolished by co-administration of ILra, an IL-1beta receptor blocker. The magnitude of inhibition of I(A) and I(K) currents by IL-1beta was significantly greater in inflamed rats than in controls. IL-1beta inhibited I(A) to a significantly greater extent than I(K). These results suggest that the inhibitory effect of I(A) and I(K) currents by IL-1beta in small-diameter TRG neurons potentiates neuronal excitability thereby contributing to trigeminal inflammatory hyperalgesia. These findings provide evidence for the development of voltage-gated K(+) channel openers and IL-1beta antagonists as therapeutic agents for the treatment of trigeminal inflammatory hyperalgesia.

The effects of ibuprofen and the neurokinin-1 receptor antagonist GR205171A on Fos expression in the ferret trigeminal nucleus following tooth pulp stimulation.

We have developed a model to study central changes following inflammation of the tooth pulp in the ferret and have examined Fos expression in the trigeminal nucleus following stimulation of non-inflamed and inflamed tooth pulps. The aim of this study was to establish the ability of this model to predict analgesic efficacy in clinical studies of inflammatory pain. We addressed this by assessing the effects of the neurokinin-1 receptor antagonist GR205171A and ibuprofen on Fos expression following stimulation of the inflamed pulp and comparing this with known analgesic efficacy. Adult ferrets were prepared under anaesthesia to allow tooth pulp stimulation, recording from the digastric muscle and intravenous injections at a subsequent experiment. In some animals pulpal inflammation was induced, by introducing human caries into a deep buccal cavity. After 5 days, animals were reanaesthetised, treated with vehicle, GR205171A or ibuprofen and the teeth were stimulated at ten times the threshold of the jaw-opening reflex. Stimulation of all tooth pulps induced ipsilateral Fos in trigeminal subnuclei caudalis and oralis. GR205171A had no significant effect on Fos expression in the trigeminal nucleus of animals with either non-inflamed or inflamed tooth pulps. Ibuprofen reduced Fos expression in the trigeminal nucleus and this effect was most marked in animals with pulpal inflammation. These results differ from those previously described using a range of other animal models, but agree with known clinical efficacy of neurokinin-1 receptor antagonists and ibuprofen. Therefore this model is likely to be of use in accurately predicting the analgesic efficacy of novel compounds.

A 12-month prospective study of gasserian ganglion stimulation for trigeminal neuropathic pain.

AIMS: Trigeminal neuropathic pain is a broad diagnostic category that includes pain of several etiologies and excludes trigeminal neuralgia. The authors report a prospective series of percutaneous gasserian ganglion stimulation for trigeminal neuropathic pain. METHODS: Patients who experienced >50% reduction in pain from a 7- to 10-day trial period underwent permanent implantation and were prospectively followed. RESULTS: Eight of 10 trialed patients received a permanent implant. At the 12-month follow-up, 2 patients had been explanted and 1 was lost to follow-up. Three (all working at that the time) continued to experience >50% improvement in pain. DISCUSSION: The results in this series were variable but 3 patients showed long-term improvements. Patients who continued to work responded better to treatment.

Management of neuropathic orofacial pain.

Current management of painful trigeminal neuropathies relies on pharmacological (topical and systemic), surgical, and complementary modalities. There is, however, a lack of quality research relating to the effectiveness of these modalities. In this review we analyze the available data that relates to the therapy of trigeminal neuralgia, postherpetic neuralgia, and posttraumatic neuropathies and provide clinical guidelines. The review focuses on medical management, as well as surgical and other interventions for painful neuropathies.

Prospective controlled trial of gamma knife surgery for essential trigeminal neuralgia.

OBJECT: Stereotactic radiosurgery is an alternative to conventional surgery for the treatment of trigeminal neuralgia. The authors conducted a prospective evaluation of the safety and efficacy of this method in a large series of patients. METHODS: A total of 100 patients presenting with trigeminal neuralgia were treated and followed up for a minimum of 12 months. The mean age was 68.2 years; 54 patients were male, and 46 were female. Seven had a history of multiple sclerosis, and 42 had already received conventional surgical treatment for trigeminal neuralgia. The intervention consisted of gamma knife surgery to the retrogasserian cisternal portion of the fifth cranial nerve. The median dose used at the maximum was 85 Gy (range 70-90 Gy). The number and intensity of pain attacks were recorded by the patient from 3 months before radiosurgery to a minimum of 12 months after treatment. Before and a minimum of 12 months after treatment, the patient completed a quality-of-life questionnaire. Neurological examination and quantitative sensory testing to evaluate sensory perception were performed by an independent neurologist over this same time period. At the last visit 83 of 100 patients were reported to be pain free. Fifty-eight of these 83 patients had stopped taking medication during the study. All quality-of-life parameters were improved (p < 0.001). Six patients reported facial paresthesia, and four patients reported hypesthesia. These symptoms were classified as mild. None of the complications reported for other techniques were observed. CONCLUSIONS: Radiosurgery is a safe and effective alternative treatment for trigeminal neuralgia and is associated with a particularly low rate of hypesthesia.