Twelve-year results of LINAC-based radiosurgery for vestibular schwannomas.

PURPOSE: To report long-term outcomes of 53 patients with vestibular schwannomas (VS) submitted to a single high-dose LINAC-based radiosurgery (SRS) in our institution. METHODS: 48 (92%) patients were evaluable for clinical and MRI response as well as late toxicity. At a median follow-up of 12 years (range 2-16 years), local control (LC), hearing capacity, trigeminal and facial nerve function, and toxicity were assessed. Hearing capacity was classified according to the Gardner-Robertson scale, where class I-II patients had "serviceable hearing." RESULTS: Median dose of SRS was 16.5 Gy (range 13-20 Gy) and median tumor volume 1.7 cm3 (range 0.09-7.4 cm3). 35 (73%) patients were treated with SRS alone, in the remaining 13 (27%) patients, SRS was performed as salvage therapy for recurrent or progressive tumors after previous microsurgery. Before SRS, 44 patients (92%) had hearing loss and 25 (52%) had "non-serviceable" hearing. Tumor extension, classified with Koos categories, was grade I-II in 27 (56%) and grade III-IV in 21 (44%) cases. LC was 100% and hearing preservation in "serviceable hearing" patients was 91%. 4 (11%) patients developed incomplete and intermittent ipsilateral facial nerve palsy which regressed in a median time of 6 months. Trigeminal toxicity was registered in 11 (23%) patients, reversible in 6 (13%) and permanent in 5 (10%). Only Koos tumor grade III-IV significantly influenced late toxicity (p = 0.01). CONCLUSION: LC and hearing preservation after SRS were excellent. Toxicity proved acceptable. Although the median administered dose (16.5 Gy) was rather high, the only factor which significantly influenced late toxicity was Koos tumor grade III-IV.

Time course of pain response and toxicity after whole-nerve-encompassing LINAC-based stereotactic radiosurgery for trigeminal neuralgia-a prospective observational study.

PURPOSE: To prospectively evaluate the time course of pain response and toxicity after linear accelerator-based whole-nerve-encompassing radiosurgery (LINAC-SRS) using a uniform treatment schedule for dosing and target volume definition in patients with refractory trigeminal neuralgia. METHODS: From December 2012 to December 2016, 21 patients were treated using a standardized protocol. Patients received LINAC-SRS with 70 Gy to the cisternal portion while aiming for the 90% isodose to fully envelope the nerve in one cross-sectional plane. Data on pain, analgesics, and toxicity were gathered prospectively. Four time intervals (1-6, 6-12, 12-18, and 18-24 months) were defined and compared to baseline and each other. RESULTS: The median follow-up from radiotherapy was 16 months. Freedom from pain was achieved at least once in 90.5, 81.0, and 85.7% of patients for everyday pain, rest pain, and pain peaks, respectively. At 1-6 months, pain was significantly reduced in everyday routine (mean VAS, 2.0/10 vs. 5.8/10; P = 0.004), at rest (1.5/10 vs. 4.0/10; P = 0.002), and for pain peaks (2.9/10 vs. 10/10; P < 0.001), as was the number of analgesics (mean 1.5 vs. 2.9; P < 0.001). No significant increase in pain or analgesics was observed for subsequent time intervals. At last follow-up, reduction in pain compared to baseline for everyday routine (2.1/10 vs. 5.8/10; P = 0.010) and for pain peaks (3.3/10 vs. 10/10; P < 0.001) was significant, whereas it was not for rest pain (1.8/10 vs. 3.9/10; P = 0.073). Most toxicities were related to trigeminal nerve impairment, with 42.9% reporting new-onset hypoesthesia at last follow-up. CONCLUSION: This study provides prospective data after whole nerve encompassing LINAC-SRS for trigeminal neuralgia. No significant pain relapse was observed.

The magnetite-based receptors in the beak of birds and their role in avian navigation.

Iron-rich structures have been described in the beak of homing pigeons, chickens and several species of migratory birds and interpreted as magnetoreceptors. Here, we will briefly review findings associated with these receptors that throw light on their nature, their function and their role in avian navigation. Electrophysiological recordings from the ophthalmic nerve, behavioral studies and a ZENK-study indicate that the trigeminal system, the nerves innervating the beak, mediate information on magnetic changes, with the electrophysiological study suggesting that these are changes in intensity. Behavioral studies support the involvement of magnetite and the trigeminal system in magnetoreception, but clearly show that the inclination compass normally used by birds represents a separate system. However, if this compass is disrupted by certain light conditions, migrating birds show 'fixed direction' responses to the magnetic field, which originate in the receptors in the beak. Together, these findings point out that there are magnetite-based magnetoreceptors located in the upper beak close to the skin. Their natural function appears to be recording magnetic intensity and thus providing one component of the multi-factorial 'navigational map' of birds.

[First experience of stereotactic radiation therapy for vestibular schwannoma using CyberKnife].

Currently stereotactic radiosurgery has become the treatment of choice in small vestibular schwannomas. This paper discusses our first experience of application of CyberKnife system for stereotactic irradiation of these tumors. From April 2009 till June 2011 we treated 62 patients (35 female and 27 male) with vestibular schwannomas. Stereotactic radiosurgery using CyberKnife system was performed in 33 patients. Mean tumor volume was 2 +/- 1.4 cm3. Hypofractionated treatment was used in 30 cases (31 tumor). Mean tumor volume reached was 7 +/- 6.2 cm3 (range - 0.5-31.3 cm3). In a case of a patient with NF2 simultaneous irradiation of bilateral tumors was performed. Most frequently we applied 3 fractions 6 Gy each (17 observations of 31, or 55%) and 5 fractions with mean dose 5 Cy (10 cases, or 32%). Follow-up period varied from 1 to 26 months (mean 9 +/- 4.5 months). By the end of this study (June 30, 2011) surgical resection was required in the only case of 47-years old male patient with cystic schwannoma of left vestibular nerve 5 months after radiation treatment, due to progressive growth of the cyst and increased brainstem compression. Tumor growth control was established in 97.5% of cases. Stabilization of auditory function was achieved in 77.5% of series. Effective hearing was preserved in 75% of patients. Facial nerve palsy after stereotactic radiation treatment was observed in 2 cases (3%). Incidence of trigeminal nerve dysfunction was significantly higher: sensation disturbances occurred in 6 (10%) patients: 3% after radiosurgery and 16.7% after hypofractionation. We did not obtain significant correlations between risk of cranial nerve complications and dosimetric or demographic factors. However we observed stable tendency: larger initial volume of the tumor and presence of trigeminal nerve dysfunction before treatment were poor prognostic factors for trigeminal neuropathy. Stereotactic irradiation using CyberKnife system is effective and sufficiently safe technique for management of vestibular schwannoma. The paper demonstrates high rates of tumor stabilization, hearing preservation and minimal incidence of complications associated with trigeminal or facial nerve.

Simultaneous Treatment of Petroclival Meningiomas and the Trigeminal Nerve with Gamma Knife Radiosurgery for Tumor-Related Trigeminal Neuralgia.

BACKGROUND: Some petroclival meningiomas cause trigeminal nerve compression, leading to disabling trigeminal neuralgia (TN). Tumor resection and nerve decompression can offer pain relief but might not be feasible in all patients. Simultaneous stereotactic radiosurgery (SRS) to the tumor and nerve is another option. SRS is an effective means of treating meningiomas and TN separately, but data on the efficacy and outcomes of their concomitant treatment are limited. CASE DESCRIPTION: We report a series of 4 patients who presented with TN secondary to a petroclival mass causing compression of the trigeminal nerve. All patients underwent SRS to both the petroclival mass and trigeminal nerve in a single session. The average margin tumor dose was 12.25 Gy (range, 12-12.5 Gy), and the average maximum trigeminal nerve dose was 80 Gy (range, 75-85 Gy). In all patients, before intervention, the Barrow Neurologic Institute (BNI) pain intensity score was grade IV or V. At last follow-up (average, 29.8 months), all patients were pain-free (BNI I or IIIA). Two patients experienced reduced facial sensation in 1 or all 3 distributions. No brainstem edema was seen. CONCLUSIONS: This series highlights the benefits and safety of simultaneous treatment of petroclival tumors and the trigeminal nerve in a single session for patients affected by tumor-related TN.

Optimizing Radiosurgery for Trigeminal Neuralgia: Impact of Radiation Dose and Anatomic Target on Patient Outcomes.

OBJECTIVE: Radiosurgery is an increasingly popular treatment for trigeminal neuralgia (TN); however, several treatment variables require further study. This meta-analysis was conducted to clarify ambiguity in the literature and optimize treatment parameters. METHODS: A random-effects proportions meta-analysis using subgroup analysis and meta-regression investigated the association of prescription dose and anatomic target on outcomes in patients with typical TN. The PRISMA guidelines were used. Radiation doses used ranged from 70 to 90 Gy and the anatomic targets were either the root entry zone or a more distal nerve location. Outcome measures were pain at last follow-up and the development of bothersome numbness. RESULTS: Increasing radiation prescription dose was associated with improved outcomes across all analyzed doses (P < 0.001). Patients treated at a distal trigeminal nerve target had better pain control compared with a root entry zone target (P < 0.001). Despite a higher median dose, a distal target was independently associated with improved pain control. There were similar rates of bothersome numbness across radiation doses and both treatment targets. CONCLUSIONS: Higher radiation dose was associated with superior pain control without increasing bothersome numbness. Independent of dose, the distal target was also associated with improved pain control. Bothersome numbness was not related to dose or target.

Synthesis, photolysis studies and in vitro photorelease of caged TRPV1 agonists and antagonists.

The synthesis of a range of caged TRPV1 agonists and antagonists is reported. The photolysis characteristics of these compounds, when irradiated with a 355 nm laser, have been studied and in all cases the desired compound was produced. Photolysis of a caged TRPV1 agonist in cultured trigeminal neurons produced responses that were consistent with the activation of TRPV1 receptors.

Experimental analysis of radiation dose distribution in radiosurgery. II. Dose fall-off outside the target volume.

INTRODUCTION: The role of radiation dose delivered to surrounding tissues outside target is often minimized in radiosurgery. We study histopathological effects of dose fall-offs outside the target using an experimental model of trigeminal nerve irradiation in the rat. MATERIAL AND METHODS: Sixteen rats were irradiated with a Gamma Knife at the right trigeminal nerve using a 90-Gy dose and 4 different gradients of dose fall-off; the brainstem at the trigeminal nerve root entry was histologically analyzed 3 months after irradiation. RESULTS: Four specific histopathological reactions were found as a consequence of the irradiation. All these reactions were significantly related to the gradient of dose fall-off. CONCLUSIONS: Different dose distributions outside the target could produce various histological effects in the irradiated tissue that could influence the outcome of radiosurgical treatment. A more rapid fall-off of dose (higher selectivity) is associated with less risk of histological changes in tissues surrounding the target.

Evolution in the assessment and management of trigeminal schwannoma.

EDUCATIONAL OBJECTIVE: At the conclusion of this presentation, the participants should be able to understand the contemporary assessment and management algorithm used in the evaluation and care of patients with trigeminal schwannomas. OBJECTIVES: 1) Describe the contemporary neuroradiographic studies for the assessment of trigeminal schwannoma; 2) review the complex skull base osteology involved with these lesions; and 3) describe a contemporary management algorithm. STUDY DESIGN: Retrospective review of 23 cases. METHODS: Chart review. RESULTS: From 1984 to 2006, of 23 patients with trigeminal schwannoma (10 males and 13 females, ages 14-77 years), 15 patients underwent combined transpetrosal extirpation, 5 patients underwent stereotactic radiation, and 3 were followed without intervention. Of the 15 who underwent surgery, total tumor removal was achieved in 9 patients. Cytoreductive surgery was performed in six patients; of these, four received postoperative radiation. One patient who underwent primary radiation therapy required subsequent surgery. There were no deaths in this series. Cranial neuropathies were present in 14 patients pretreatment and observed in 17 patients posttreatment. Major complications included meningitis (1), cerebrospinal fluid leakage (2), major venous occlusion (1), and temporal lobe infarction (1). CONCLUSIONS: Trigeminal schwannomas are uncommon lesions of the skull base that may occur in the middle fossa, posterior fossa, or both. Moreover, caudal extension results in their presentation in the infratemporal fossa. Contemporary diagnostic imaging, coupled with selective use of both surgery and radiation will limit morbidity and allow for the safe and prudent management of this uncommon lesion.

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.

Peculiar geometric alopecia and trigeminal nerve dysfunction in a patient after Guglielmi detachable coil embolization of a ruptured aneurysm.

Neuroendovascular treatment is increasingly being used for treatment of intracranial aneurysms. Postradiation alopecia, commonly seen weeks after radiation for other diseases such as brain tumors, is rarely reported after neuroendovascular procedures for benign lesions because of their delayed manifestations. Although the morbidity and mortality is less compared with surgery, adverse effects related to radiation are probably understated, underreported, and/or often attributed to prolonged bed rest, heparinization, or poor nutrition. We present a case with a delayed onset of a graphic but peculiar geometric alopecia associated with trigeminal nerve pattern dysfunction, which was related to the fluoroscopic radiation for coil embolization of an anterior communicating artery aneurysm.

Effect of Laser Photobiomodulation with Gradual or Constant Doses in the Regeneration of Rats' Mental Nerve After Lesion by Compression.

OBJECTIVE: Assess morphologically the efficacy of constant dose (CD) or gradual dose (GD) in photobiomodulation therapy (PBMT) during the regeneration process of rats' mental nerve after compression lesion. MATERIALS AND METHODS: Forty-eight male Wistar rats were used and divided into four groups (n = 12): negative control (NC): lesion by compression; positive control (PC): no lesion; GD: lesion by compression and PBMT with GD; and CD: lesion by compression and PBMT with CD. One day after the surgery, the groups GD and CD underwent PBMT daily in three equidistant points around the incision area. The parameters were wavelength of 808 nm, 100 mW, CD received treatment with 120 J/cm2, while GD underwent the protocol of application: 1st and 4th sessions: 80 J/cm2; 5th to 8th sessions: 90 J/cm2; 9th to 12th sessions: 100 J/cm2; 13th to 16th sessions: 110 J/cm2; and 17th to 20th sessions: 120 J/cm2. Euthanasias were performed at 3, 7, 14, and 21 days. Qualitative and quantitative analysis of the mental nerves were performed with ANOVA (analysis of variance) and Tukey tests (p ≤ 0.05). RESULTS: It was observed that PBMT was able to accelerate the process of nerve regeneration presenting an increase in the number of myelinated fibers starting at 14 days of treatment for groups CD and GD, and at 21 days they were similar to PC. It was observed a better lamellar organization of myelin sheath at 7 days for GD and at 14 days for CD, similar to PC. Both GD and CD presented significant differences compared to NC and PC for thickness of the myelin sheath, outer perimeter, internal area, and number of myelin fibers. CONCLUSIONS: PBMT presented positive effect on the regeneration of nerve starting at 14 days, and after 21 days there was no difference between GD and CD.

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.

Chemosensory event-related potentials during sleep--a pilot study.

Aim of the present pilot study was to investigate whether cortically generated chemosensory event-related potentials (ERPs) can be recorded during sleep. Chemosensory function during sleep was assessed in 14 healthy female volunteers. An overnight polysomnography was performed to assess nocturnal sleep and to classify sleep stages. Chemosensory ERPs were recorded using air-dilution olfactometry. H2S (4ppm) was used for olfactory and CO2 (40%, v/v) for trigeminal stimulation. Chemosensory ERPs could be recorded during sleep for both olfactory and trigeminal stimuli in some but not all subjects. Compared to baseline, latencies of olfactory ERPs were longer and amplitudes were larger during light sleep and slow wave sleep (SWS). For trigeminal stimulation N1 latencies were longest during REM sleep. These results indicate that both trigeminal and olfactory ERPs can be recorded during sleep suggesting that chemosensory stimuli are processed on a cortical level during sleep.

Localization and properties of respiratory neurons in the rostral pons of the newborn rat.

The distribution and discharge pattern of respiratory neurons in the 'pneumotaxic center' of the rostral pons in the rat has remained unknown. We performed optical recordings and whole-cell patch clamp recordings to clarify respiratory neuron activity in the rostral pons of a brainstem-spinal cord preparation from a newborn rat. Inspiratory nerve activity was recorded in the 4th cervical nerve and used as a trigger signal for optical recordings. Respiratory neuron activity was detected in the limited region of the rostral-lateral pons. The main active region was presumed to be primarily the Kölliker-Fuse nucleus. The location of respiratory neurons was further confirmed by Lucifer Yellow staining after conducting whole-cell recordings. From a membrane potential analysis of the respiratory neurons in the rostral pons, the respiratory neurons were divided into four types: inspiratory neuron (71.9%), pre-inspiratory neuron (5.3%), post-inspiratory neuron (19.3%), and expiratory neuron (3.5%). A noticeable difference between pontine and medullary respiratory neurons was that post-inspiratory neurons were more frequently encountered in the pons. Application of a mu-opioid agonist, [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin, transformed the burst pattern of post-inspiratory neurons into that of pre-inspiratory neurons. The electrical stimulation of the sensory root of the trigeminal nerve induced three types of responses in 85% of pontine respiratory neurons: inhibitory postsynaptic potentials (42.7%), excitatory postsynaptic potentials (37.7%) and no response (15.1%). Our findings provide the first evidence in the rat for the presence of respiratory neurons in the rostral pons, with localization in the lateral region approximately overlapping with the Kölliker-Fuse nucleus.

Differential activation of trigeminal C or Adelta nociceptors by infrared diode laser in rats: behavioral evidence.

Radiant heat is often used for studying thermal nociception, although inherent characteristics such as the broad spectrum of applied wavelengths of typical light sources limit control over and repeatability of stimuli. To overcome these problems, we used a diode infrared laser-based stimulator (wavelength: 980 nm) for selectively stimulating trigeminal Adelta or C thermonociceptors in rats. To provide indirect evidence for nociceptor-selective stimulation, we tested the effects of capsaicin, dimethylsulfoxide (DMSO), and morphine on withdrawal latencies for long pulses with a low current (hypothesized to selectively stimulate C nociceptors) and for threshold currents of short pulses with high current (hypothesized to selectively stimulate Adelta nociceptors) in lightly anesthetized rats. Nonmem analysis was used to perform pharmacodynamic modeling. The measured baseline withdrawal latency for long pulses was 12.5 +/- 0.3 s which was changed significantly to 6.7 +/- 0.4 s after applying topical capsaicin which selectively sensitizes C nociceptors and to 16.5 +/- 1.3 s after 1.0 mg/kg morphine which preferentially attenuates C fiber nociception. Topical DMSO which appears to selectively sensitize Adelta afferents did not significantly alter withdrawal latencies to the long pulses. Fitted threshold currents for short pulses after DMSO were however significantly lower (974 +/- 53 mA vs. 1113 +/- 12 mA for baseline) indicating Adelta sensitization. Capsaicin and morphine did not significantly change threshold currents. Best Nonmem fits for the long pulse were obtained using a model assuming no DMSO effect, but a different inter-individual variability after applying this substance. For the short pulse, a model assuming no capsaicin or morphine effect, but again allowing different inter-individual variabilities after applying these drugs, best described the data. We conclude that different settings of the stimulator used in this study were capable of selectively activating trigeminal Adelta or C thermonociceptors.

Changes in sensory and pain perception thresholds after linear polarized near-infrared light radiation in the trigeminal region.

Linearly polarized light in the near-infrared portion of the spectrum has recently been associated with a variety of musculoskeletal disorders including temporomandibular disorders. The purpose of this study was to determine whether short-term linearly polarized near-infrared light radiation in the trigeminal region affects sensory and pain perception thresholds in the trigeminally mediated region and in the cervically mediated region of normal subjects. Thirty-five normal female volunteers participated in this study. Each subject received an 8-minute course of irradiation in the right cheek, and sensory/nociceptive perception thresholds were compared before and immediately after the irradiation in the right cheek and the right forearm. As a result, this study demonstrated a significant elevation of the heat-induced pain threshold in both regions and a tendency for the warm sensation threshold to elevate in the cervical region. In addition, a significant increase in vibratory sensitivity was observed in the trigeminal region. In conclusion, our results provided additional evidence that the warming sensation has a negative feedback influence on heat pain intensity in humans, and provides a theoretical basis for the application of linear polarized near-infrared light radiation to the trigeminal region.

Post-irradiation neuromyotonia affecting trigeminal nerve distribution: an unusual presentation.

We describe two patients who developed neuromyotonia of the floor of the mouth after irradiation of a motor branch (V3) of the trigeminal nerve. The neuromyotonia manifested as sustained muscle contraction due to peripheral nerve dysfunction. The neuromyotonia in both patients was controlled with carbamazepine. Radiation-exposed nerves can become symptomatic months or years after completion of radiation therapy.

Local application of the cannabinoid receptor agonist, WIN 55,212-2, to spinal trigeminal nucleus caudalis differentially affects nociceptive and non-nociceptive neurons.

Cannabinoid receptor agonists produce analgesia for pains of non-cranial origin. However, their effectiveness for craniofacial pains is currently unclear. In the present study, the cannabinoid CB1/CB2 receptor agonist, WIN 55,212-2 (WIN), was bath applied to the brainstem while activity of spinal trigeminal nucleus caudalis (Vc) neurons evoked by transcutaneous electrical stimulation was recorded in isoflurane anesthetized rats. Neurons were characterized using mechanical and electrical stimulation of the face, and were classified as either low-threshold mechanoreceptive (LTM) or wide dynamic range (WDR). LTM neurons responded to light brushing of the receptive field and received only Abeta primary afferent fiber input. WDR neurons showed a graded response to mechanical stimulation, responding maximally to noxious stimuli, and demonstrated both A- and C-fiber evoked activity. In addition, WDR neurons displayed longer latency, C-fiber mediated post-discharge (PDC) activity after repetitive stimulation. Local bath application of 2.0 mg/ml WIN significantly reduced PDC activity (3+/-1% control, P<0.01), C-fiber evoked activity (58+/-9% control, P<0.01), and Abeta evoked activity (57+/-10% control, P<0.01) in WDR neurons. In contrast, LTM Abeta-fiber evoked activity increased after local administration of WIN (204+/-52% control, P<0.01). SR141716A, a CB1 receptor antagonist, prevented the effects of WIN on WDR PDC and LTM Abeta evoked activity. These results indicate that cannabinoid receptor agonists may be effective agents for craniofacial pain. Furthermore, the particular sensitivity of PDC activity, a measure of neuronal hyperexcitability, to cannabinoid receptor agonists may be relevant to the treatment of persistent craniofacial pain.

Modulation of trigeminal laser evoked potentials and laser silent periods by homotopical experimental pain.

Cutaneous laser stimulation activates predominantly the A-delta and C mechano-heat nociceptors. Applied to the perioral region, low intensity CO(2)-laser pulses evoke reproducible trigeminal cortical evoked potentials (LEPs). High intensity CO(2)-laser stimuli induce a reflex response in the contracted jaw-closing muscle, the so-called laser silent period (LSP). Both LEPs and LSP provide a useful tool to study the physiology of the trigeminal nociceptive system. In ten healthy subjects we recorded the subjective ratings of the perioral laser stimulation and the trigeminal LEPs and LSP before, during and after homotopic experimental tonic muscle (infusion of hypertonic saline into the masseter muscle) and tonic skin pain (topical application of capsaicin to the cheek). LEPs were recorded from the vertex at two stimulus intensities: low (1.1 x pain threshold, PTh) and high (1.5 x PTh). LSP from masseter and temporalis muscles were recorded bilaterally through surface electromyographic (EMG) electrodes. CO(2)-laser pulses were applied to the perioral region (V2/V3) on the painful and non-painful side. The amplitude of LEPs increased with higher stimulus intensities (P<0.0001), but were suppressed by 42.3+/-5.3% during experimental muscle pain (P<0.0001) and by 41.6+/-3.2% during skin pain (P<0.0001). No pain-related effects were observed for the N and P latency of the LEPs (P> 0.20). The LSP in the masseter and temporalis muscles had similar onset-latency (80+/-5 ms), offset-latency (111+/-5 ms) and duration (31+/-4 ms). Experimental pain had no effect on the onset- and offset-latency (P>0.05). Experimental pain, whether from muscle or from skin, reduced the degree of suppression (P<0.01) and the area under the EMG curve (P< 0.005) of the LSP. The LSP was still suppressed during the post-pain recordings when the skin pain had disappeared (P<0.05). In all experiments experimental tonic pain decreased the subjective ratings of the perioral laser stimulation (P< 0.001). Experimental tonic pain, either from muscle or from skin, induced bilateral inhibitory effects on the trigeminal laser evoked potentials and brainstem reflex responses and on the subjective ratings of the laser pulses. These effects could be mediated through the activation of segmental and suprasegmental inhibitory systems that may function interdependently.