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Background: Spinal cord stimulation (SCS) is an established treatment option for patients with refractory chronic pain conditions. While effects of SCS on dorsal horn neuronal circuitries are intensively studied, current knowledge on the impact of SCS on descending pain pathways is scarce and relies on preclinical data. We aimed to address this topic and hypothesized a significant effect of SCS on descending pain modulation. In light of current efforts to determine the sensitivity of “static” versus “dynamic” somatosensory parameters to characterize pathophysiological pain conditions, all SCS patients were carefully investigated using both classes of somatosensory outcome parameters.Methods: Descending pain pathways were investigated by using a “Cold Pressor Test.” This test enables to evaluate the efficacy of conditioned pain modulation (CPM) at the individual level. CPM efficacy was assessed in eight neuropathic pain patients (age 55.5 ± 10.6) during the two conditions stimulator “ON” and “OFF.” The impact of SCS on “static” and “dynamic” somatosensory parameters was explored by using a quantitative sensory testing (QST) battery.Results: CPM efficacy on pressure pain sensitivity was nearly absent during “OFF” (− 1.2 ± 5.6% facilitation), but increased significantly to 16.3 ± 3.4% inhibition during “ON” (p = 0.03). While most “static” nociceptive QST parameters, represented by mechanical/thermal pain thresholds, exhibited only small effects of SCS (p > 0.05), the wind-up ratio was strongly reduced to within the normal range during “ON” (p = 0.04; Cohen’s d = 1.0). Dynamic mechanical allodynia was abolished in six of seven patients.Conclusions: Our study provides first human evidence for an impact of SCS on descending pain pathways in the dorsolateral funiculus and emphasizes the significance of “dynamic” pain measures like “CPM”-efficacy and “temporal summation” to evaluate SCS treatment effects. Future prospective studies may use these measures of nociceptive processing to predict SCS therapy response. [ABSTRACT FROM AUTHOR]

Abstract: Sleep disturbances are highly prevalent in chronic pain patients. Understanding their relationship has become an important research topic since poor sleep and pain are assumed to closely interact. To date, human experimental studies exploring the impact of sleep disruption/deprivation on pain perception have yielded conflicting results. This inconsistency may be due to the large heterogeneity of study populations and study protocols previously used. In addition, none of the previous studies investigated the entire spectrum of nociceptive modalities. To address these shortcomings, a standardized comprehensive quantitative sensory protocol was used in order to compare the somatosensory profile of 14 healthy subjects (6 female, 8 male, 23.5±4.1year; mean±SD) after a night of total sleep deprivation (TSD) and a night of habitual sleep in a cross-over design. One night of TSD significantly increased the level of sleepiness (P <0.001) and resulted in higher scores of the State Anxiety Inventory (P <0.01). In addition to previously reported hyperalgesia to heat (P <0.05) and blunt pressure (P <0.05), study participants developed hyperalgesia to cold (P <0.01) and increased mechanical pain sensitivity to pinprick stimuli (P <0.05) but no changes in temporal summation. Paradoxical heat sensations or dynamic mechanical allodynia were absent. TSD selectively modulated nociception, since detection thresholds of non-nociceptive modalities remained unchanged. Our findings show that a single night of TSD is able to induce generalized hyperalgesia and to increase State Anxiety scores. In the future, TSD may serve as a translational pain model to elucidate the pathomechanisms underlying the hyperalgesic effect of sleep disturbances. [Copyright &y& Elsevier]

For decades, serotonin has been speculated to play a major role in migraine pathophysiology. The central serotonergic system is located in the raphe nuclei and the adjacent reticular formation in the brainstem. Recently, radioligands targeting the brain serotonin transport protein (SERT) have been developed. We used the highly specific SERT-radioligand 123I-ADAM [2-((2-((dimethylamino) methyl)phenyl)thio)-5-iodophenylamine] to test the hypothesis of the mesopontine serotonergic system being involved in the pathophysiology of migraine. Nineteen migraine patients and 10 healthy, age- and sex-matched controls were enrolled. The neuroimaging study was performed interictally during the pain-free interval. Single Photon Emission Computed Tomography (SPECT)-images were coregistered with MRI-scans. Region of interest (ROI)-analysis revealed a highly significant increase of 123I-ADAM uptake in the mesopontine brainstem of migraineurs (p < 0.001). In contrast, 123IADAM uptake in the thalamus did not differ significantly between migraineurs and controls. Our study demonstrates for the first time a significant increase of brainstem SERT-availability in migraineurs, suggesting a dysregulation of the brainstem serotonergic system. It remains to be elucidated whether the altered SERT-availability is causally related to migraine pathophysiology or whether it reflects secondary pathophysiological mechanisms. [ABSTRACT FROM AUTHOR]

Objective.—We aimed to study the effect of normobaric hyperoxia on neurogenic inflammation of the rat dura mater. Background.—Inhalation of 100% oxygen is a first-line therapy for the treatment of acute cluster headache (CH). However, the mechanisms underlying the antinociceptive effect of oxygen are poorly understood. Sumatriptan, which is also effective in aborting CH attacks, is known to inhibit neurogenic inflammation of the dura mater. We hypothesized that hyperoxia reduces dural plasma protein extravasation in the model of electrically stimulating the rat trigeminal ganglion. Methods.—Unilateral stimulation of the trigeminal ganglion was performed in anesthetized male Sprague-Dawley rats. We assessed plasma protein extravasation (PPE) in the ipsilateral dura mater under normoxic (group 1) and hyperoxic conditions (group 2: pO2 200 mmHg; group 3: pO2 300 mmHg; group 4: pO2 400 mmHg). The study results were compared to the effect of sumatriptan (300 μg/kg) on dural PPE. Results.—Under normoxic conditions, the calculated extravasation ratio was 1.72 ± 0.2. Hyperoxic treatment (groups 2, 3, 4) significantly attenuated dural PPE. At oxygen levels of 400 mmHg, the PPE ratio was 1.14 ± 0.2 ( P < .01). After IV application of sumatriptan (300 μg/kg), PPE was nearly abolished (PPE ratio: 1.06 ±0.17). Conclusion.—Our findings demonstrate that hyperoxia is able to inhibit dural PPE. Hyperoxia may play an anti-inflammatory role in neurogenic inflammation, but further studies are needed to clarify whether this effect is either caused by prejunctional mechanisms or by modulation of the vascular permeability at postcapillary venules. [ABSTRACT FROM AUTHOR]

Objective.—We aimed to investigate the effects of the cyclooxygenases-2 (COX-2) inhibitor parecoxib on meningeal plasma protein extravasation (PPE) and on c-fos expression in the nucleus trigeminalis caudalis in an animal model of trigeminova scular activation. Background.—Recent reports about the efficacy of COX-2 inhibitors in migraine treatment suggest the involvement of COX-2 in migraine pathophysiology. So far, studies on the role of COX-2 in animal models of migraine are lacking. Methods.—Unilateral electrical stimulation of the trigeminal ganglion was performed in anesthetized male Sprague Dawley rats. We assessed PPE in the ipsilateral dura mater and expression of c-fos within the ipsilateral trigeminal nucleus caudalis (TNC) under control conditions and after pretreatment with parecoxib. Results.—Parecoxib significantly attenuated PPE in the rat dura mater. The PPE ratio under control conditions (1.73 ± 0.19 (mean ± SD)) was reduced by 58.9 ± 30% after pretreatment with 10 mg/kg parecoxib and by 78.1 ± 23% after pretreatment with 50 mg/kg. c-fos experiments: Compared with vehicle, all doses of parecoxib (1 mg/kg, 10 mg/kg, 50 mg/kg) significantly reduced the number of c-fos positive cells in the ipsilateral TNC ( P < .05). The number of c-fos positive cells in the ipsilateral TNC was 50 ± 2.7 (mean ± SEM) under control conditions and 9.1 ± 0.6 after pretreatment with 50 mg/kg parecoxib. Conclusion.—Our study results suggest that COX-2 is involved in neurogenic inflammation of the rat dura mater. Moreover, the study points to a role of COX-2 inhibitors in trigeminal nociception at the second-order level. [ABSTRACT FROM AUTHOR]

We describe a nonradioactive, fluorescence-based method to assess plasma protein extravasation (PPE) in rat dura mater using confocal laser scanning microscopy (CLSM). Unilateral PPE can be induced by electrical stimulation of the ipsilateral trigeminal ganglion (TG) and is widely used as an experimental migraine model. The gold standard to determine PPE in the meninges is based on the detection of radiolabeled albumin ([125]I-BSA). The aim of this study was to develop a nonradioactive, histological method to quantify PPE in the meninges. The fluorescent dye Evans Blue (50 mg/kg) was injected intravenously to the rat 7 min prior to TG stimulation. PPE in dura mater was detected by a CLSM. The amount of extravasated Evans Blue in the dura mater was measured at six to eight regions of interest (ROIs) in the vicinity of large meningeal vessels. The ratio of the average fluorescence intensity within dura mater of the “stimulus side”, compared to the contralateral “control side”, was calculated for each animal. By using this method, The PPE ratio was 1.67±0.12 (n=5). Intravenous injection of three different dosages of the 5HT1B/1D-receptor agonist sumatriptan (25, 50, and 100 μg/kg) 15 min prior to stimulation attenuated PPE by 42±12%, 49±9%, and 86±15%, respectively (p<0.01). The approximated ED50 value was 48 μg/kg. Our results are in accordance with previous reports in the literature using the radioactive approach. We conclude that CLSM is a safe, sensitive, and reliable method to assess PPE in rat meninges in an experimental migaine model. [Copyright &y& Elsevier]

The concept "nociplastic pain" has been developed for patients with features of nociceptive system sensitization that are not explained as nociceptive or neuropathic. Here, we tested how well the recently published grading system differentiates between chronic primary and secondary pain conditions. We recruited patients with fibromyalgia (FMS, n = 41), complex regional pain syndrome (CRPS, n = 11), osteoarthritis (OA, n = 21), or peripheral nerve injury (PNI, n = 8). We used clinical history, pain drawings, quantitative sensory testing (QST), and questionnaires to classify their pains as possibly or probably "nociplastic." All patients with chronic primary pain exhibited widespread/regional pain not explainable by either nociceptive or neuropathic mechanisms. Widespread pain occurred in 12 patients with OA but was identified as nociceptive in 11 of 12. Regional pain occurred in 4 patients with PNI but was identified as neuropathic in 3 of 4. At this step, the grading system had 100% sensitivity and 93% specificity. Clinical evidence for pain hypersensitivity by QST, and history of hypersensitivity and mental comorbidities did not differentiate between chronic primary pain (QST: 36/52 = 69%, history: 43/52 = 83%) and secondary pain conditions (QST: 20/29 = 69%, history: 24/29 83%). Based on these data, specificity remained excellent (93%), but sensitivity dropped substantially (60%) due to lacking evidence for pain hypersensitivity in many patients with FMS. This low sensitivity suggests that the published grading system is not suitable for screening purposes. We suggest structural and content modifications to improve sensitivity, including placement of patient history before clinical examination and addition of a high tender point count as evidence for widespread pain hypersensitivity. [ABSTRACT FROM AUTHOR]

Background: Clinical trials have shown that cenobamate (CNB) is an efficacious and safe anti-seizure medication (ASM) for drug-resistant focal epilepsy. Here, we analyzed one of the largest real-world cohorts, covering the entire spectrum of epilepsy syndromes, the efficacy and safety of CNB, and resulting changes in concomitant ASMs. Methods: We conducted a retrospective observational study investigating CNB usage in two German tertiary referral centers between October 2020 and June 2023 with follow-up data up to 27 months of treatment. Our primary outcome was treatment response. Secondary outcomes comprised drug response after 12 and 18 months, seizure freedom rates, CNB dosage and retention, adverse drug reactions (ADRs), and changes in concomitant ASMs. Results: 116 patients received CNB for at least two weeks. At 6 months, 98 patients were eligible for evaluation. Thereof 50% (49/98) were responders with no relevant change at 12 and 18 months. Seizure freedom was achieved in 18.4% (18/98) at 6 months, 16.7% (11/66), and 3.0% (1/33) at 12 and 18 months. The number of previous ASMs did not affect the seizure response rate. Overall, CNB was well-tolerated, however, in 7.7% (9/116), ADRs led to treatment discontinuation. The most frequent changes of concomitant ASMs included the discontinuation or reduction of sodium channel inhibitors, clobazam reduction, and perampanel discontinuation, while brivaracetam doses were usually left unchanged. Conclusions: CNB proved to be a highly effective and generally well-tolerated ASM in patients with severe drug-resistant epilepsy, comprising a broad array of epilepsy syndromes beyond focal epilepsy. [ABSTRACT FROM AUTHOR]

Highlights • Sleep deprivation related changes of endogenous pain modulation depend on gender. • Contrary to males, descending pain inhibition of sleep deprived females is significantly reduced. • Sleep deprivation induced cold and mechanical hyperalgesia are sex-independent. • In contrast, heat pain thresholds do only significantly decrease in sleep deprived females. Abstract Sex matters both in the clinical field of pain and sleep medicine. Sleep disturbances are highly prevalent in chronic pain patients and have been shown to deteriorate the pain condition. The pathomechanisms by which insomnia aggravates pain are currently unknown. Descending pain control may be compromised by disturbed sleep, but respective studies are few, inconsistent and largely imbalanced with respect to sex. We studied the role of sex on the effect of sleep deprivation on endogenous pain modulation and on nociceptive thresholds in a highly homogenous study population of 18 female (23.8 ± 3.4 years) and 18 male (23.3 ± 2.7) healthy students. One night of total sleep deprivation (TSD) was contrasted with one night of habitual sleep in a balanced cross-over design. A cold pressor test was used to explore the effect of TSD on supraspinal pain control. The effect of TSD on nociception was examined by Quantitative Sensory Testing (QST). RM-ANOVA was used for statistical analysis. We found a sex-dependent effect of TSD on descending pain pathways, since the endogenous capacity to inhibit pain was only reduced in sleep deprived females (interaction between ‘sleep condition’ and ‘sex’: p = 0.023). While TSD-induced cold and mechanical hyperalgesia were independent of sex, heat pain thresholds did only significantly decrease in sleep deprived females (p = 0.041). Our results point to a sex specific impact of TSD on descending pain inhibition. In the future, therapeutic strategies for pain patients with co-morbid insomnia may need to more explicitly respect the specific role of sex. [ABSTRACT FROM AUTHOR]

Background and purpose: Diabetic sensorimotor peripheral neuropathy is usually considered to affect predominantly the lower limbs (LL‐N), whereas the impact of upper limb neuropathy (UL‐N) on hand functional performance and quality of life (QoL) has not been evaluated systematically. This study aims to investigate the prevalence and characteristics of UL‐N and its functional and psychosocial consequences in type 2 diabetes. Methods: Individuals with type 2 diabetes (n = 141) and an age‐ and sex‐matched control group (n = 73) underwent comprehensive assessment of neuropathy, hand functional performance, and psychosocial status. Results: The prevalence of UL‐N was 30.5% in patients with diabetes and that of LL‐N was 49.6%, with 25.5% exhibiting both. Patients with diabetes showed similar sensory phenotype regarding both large and small fiber functions in hands and feet. Patients with UL‐N showed reduced manual dexterity, but normal hand grip force. Additionally, there was a correlation between reduced dexterity and sensory deficits. Patients with UL‐N had reduced estimates of psychosocial health including health‐related QoL compared to control subjects and patients without UL‐N. UL‐N correlated with the severity of LL‐N, but not with duration of diabetes, glycemia, age, or sex. Conclusions: This study points to a substantial prevalence of UL‐N in type 2 diabetes. The sensory phenotype of patients with UL‐N was similar to LL‐N and was characterized by loss of sensory function. Our study demonstrated an association of UL‐N with impaired manual dexterity and reduced health‐related QoL. Thus, upper limb sensorimotor functions should be assessed early in patients with diabetes. [ABSTRACT FROM AUTHOR]

This correction notice is for an article titled "Cenobamate: real-world data from a retrospective multicenter study" published in the Journal of Neurology. The original article contained an incorrect abstract. The study analyzed the efficacy and safety of cenobamate (CNB), an anti-seizure medication, in a large real-world cohort of patients with various epilepsy syndromes. The primary outcome was treatment response, and secondary outcomes included seizure freedom rates, adverse drug reactions, and changes in concomitant anti-seizure medications. The study found that CNB was highly effective and generally well-tolerated in patients with drug-resistant epilepsy. [Extracted from the article]

Presents a study which investigated the role of endothelial nitric oxide synthase and neuronal nitric oxide synthase in the nitric oxide synthase-dependent vasodilation to acidosis. Materials and methods; Results; Discussion.

Studies on magnetic resonance neurography (MRN) in diabetic polyneuropathy (DPN) have found proximal sciatic nerve lesions. The aim of this study was to evaluate the functional relevance of sciatic nerve lesions in DPN, with the expectation of correlations with the impairment of large-fiber function. Sixty-one patients with type 2 diabetes (48 with and 13 without DPN) and 12 control subjects were enrolled and underwent MRN, quantitative sensory testing, and electrophysiological examinations. There were differences in mechanical detection (Aβ fibers) and mechanical pain (Aδ fibers) but not in thermal pain and thermal detection clusters (C fibers) among the groups. Lesion load correlated with lower Aα-, Aβ-, and Aδ-fiber but not with C-fiber function in all participants. Patients with lower function showed a higher load of nerve lesions than patients with elevated function or no measurable deficit despite apparent DPN. Longer diabetes duration was associated with higher lesion load in patients with DPN, suggesting that nerve lesions in DPN may accumulate over time and become clinically relevant once a critical amount of nerve fascicles is affected. Moreover, MRN is an objective method for determining lower function mainly in medium and large fibers in DPN. [ABSTRACT FROM AUTHOR]

Aims: The aim of the study was to assess whether quantitative-sensory-testing could be used to evaluate prevalence and predictors of diabetic neuropathy (DPNP) in patients with pre-diabetes and type 2 diabetes.Methods: Twenty-eight pre-diabetics and 108 patients with type 2 diabetes were evaluated using neuropathy-deficit-score (NDS), neuropathy-symptom-score (NSS), nerve-conduction-studies (NCS), short-QST-protocol to examine small fibers and the comprehensive QST-battery (long-QST) according to the German Research Network on Neuropathic Pain protocol.Results: Long-QST revealed a DPNP-prevalence of 71% in pre-diabetics and 95% in patients with type 2 diabetes, while according to NDS it was only 11% and 63%, and NCS missed 58% of patients with DPNP. Small and medium fibers were similarly affected in both groups, while large fiber deficits were significantly more common in type 2 diabetes (p < 0.01). Complete loss of function in all fibers was significantly higher in patients with type 2 diabetes than in pre-diabetics (26% vs. 11%, p < 0.05). Hyperalgesia was slightly increased in pre-diabetes than in type 2 diabetes (57% vs. 43%, p = n.s.). However, NSS only showed significant associations with large fiber deficits. Logistic regression analyses revealed that age (OR 1.14[1.05/1.24]) and albuminuria (OR 12.8[1.52/107.3]) were independent predictors for the presence of DPNP.Conclusions: DPNP is much more prevalent in patients with pre-diabetes and type 2 diabetes and clinical routine tests may miss the majority of affected patients. Age and albuminuria, but not HbA1c, appear to be significantly associated with DPNP.Clinical Trial Registration: NCT03022721. [ABSTRACT FROM AUTHOR]

As an indirect approach to relate previously identified sensory phenotypes of patients suffering from peripheral neuropathic pain to underlying mechanisms, we used a published sorting algorithm to estimate the prevalence of denervation, peripheral and central sensitization in 657 healthy subjects undergoing experimental models of nerve block (NB) (compression block and topical lidocaine), primary hyperalgesia (PH) (sunburn and topical capsaicin), or secondary hyperalgesia (intradermal capsaicin and electrical high-frequency stimulation), and in 902 patients suffering from neuropathic pain. Some of the data have been previously published. Randomized split-half analysis verified a good concordance with a priori mechanistic sensory profile assignment in the training (79%, Cohen κ = 0.54, n = 265) and the test set (81%, Cohen κ = 0.56, n = 279). Nerve blocks were characterized by pronounced thermal and mechanical sensory loss, but also mild pinprick hyperalgesia and paradoxical heat sensations. Primary hyperalgesia was characterized by pronounced gain for heat, pressure and pinprick pain, and mild thermal sensory loss. Secondary hyperalgesia was characterized by pronounced pinprick hyperalgesia and mild thermal sensory loss. Topical lidocaine plus topical capsaicin induced a combined phenotype of NB plus PH. Topical menthol was the only model with significant cold hyperalgesia. Sorting of the 902 patients into these mechanistic phenotypes led to a similar distribution as the original heuristic clustering (65% identity, Cohen κ = 0.44), but the denervation phenotype was more frequent than in heuristic clustering. These data suggest that sorting according to human surrogate models may be useful for mechanism-based stratification of neuropathic pain patients for future clinical trials, as encouraged by the European Medicines Agency. [ABSTRACT FROM AUTHOR]

In a recent cluster analysis, it has been shown that patients with peripheral neuropathic pain can be grouped into 3 sensory phenotypes based on quantitative sensory testing profiles, which are mainly characterized by either sensory loss, intact sensory function and mild thermal hyperalgesia and/or allodynia, or loss of thermal detection and mild mechanical hyperalgesia and/or allodynia. Here, we present an algorithm for allocation of individual patients to these subgroups. The algorithm is nondeterministic-ie, a patient can be sorted to more than one phenotype-and can separate patients with neuropathic pain from healthy subjects (sensitivity: 78%, specificity: 94%). We evaluated the frequency of each phenotype in a population of patients with painful diabetic polyneuropathy (n = 151), painful peripheral nerve injury (n = 335), and postherpetic neuralgia (n = 97) and propose sample sizes of study populations that need to be screened to reach a subpopulation large enough to conduct a phenotype-stratified study. The most common phenotype in diabetic polyneuropathy was sensory loss (83%), followed by mechanical hyperalgesia (75%) and thermal hyperalgesia (34%, note that percentages are overlapping and not additive). In peripheral nerve injury, frequencies were 37%, 59%, and 50%, and in postherpetic neuralgia, frequencies were 31%, 63%, and 46%. For parallel study design, either the estimated effect size of the treatment needs to be high (>0.7) or only phenotypes that are frequent in the clinical entity under study can realistically be performed. For crossover design, populations under 200 patients screened are sufficient for all phenotypes and clinical entities with a minimum estimated treatment effect size of 0.5. [ABSTRACT FROM AUTHOR]

Background: Neurosurgical pain management of drug-resistant trigeminal neuralgia (TN) is highly challenging. Microvascular decompression is a first-line neurosurgical approach for classical TN with neurovascular conflict, but can show clinical relapse despite proper decompression. Second-line destructive techniques like radiofrequency thermocoagulation have become reluctantly used due to their potential for irreversible side effects. Subcutaneous peripheral nerve field stimulation (sPNFS) is a minimally invasive neuromodulatory technique which has been shown to be effective for chronic localised pain conditions. Reports on sPNFS for the treatment of trigeminal pain (sTNFS) are still sparse and primarily focused on pain intensity as outcome measure. Detailed data on the impact of sTNFS on attack frequency are currently not available. Methods: Patients were classified according to the International Headache Society classification (ICHD-3-beta). Three patients had classical TN without ( n = 3) and another three TN with concomitant persistent facial pain ( n = 3). Two patients suffered from post-herpetic trigeminal neuropathy ( n = 2). All eight patients underwent a trial stimulation of at least 7 days with subcutaneous leads in the affected trigeminal area connected to an external neurostimulator. Of those, six patients received permanent implantation of a neurostimulator. During the follow-up (6-29 months, mean 15.2), VAS-scores, attack frequencies, oral drug intake, complications and side effects were documented. Results: Seven out of eight patients responded to sTNFS (i.e. ≥50 % pain reduction) during the test trial. The pain intensity (according to VAS) was reduced by 83 ± 16 % (mean ± SD) and the number of attacks decreased by 73 ± 26 % (mean ± SD). Five out of six patients were able to reduce or stop pain medication. One patient developed device infection. Two patients developed stimulation-related side effects which could be resolved by reprogramming. Conclusions: Treatment by sTNFS is a beneficial option for patients with refractory trigeminal pain. Prospective randomised trials are required to systematically evaluate efficacy rates and safety of this low-invasive neurosurgical technique. [ABSTRACT FROM AUTHOR]

Background: The capsaicin and heat responsive ion channel TRPV1 is expressed on trigeminal nociceptive neurons and has been implicated in the pathophysiology of migraine attacks. Here we investigate the efficacy of two TRPV1 channel antagonists in blocking trigeminal activation using two in vivo models of migraine. Methods: Male Sprague–Dawley rats were used to study the effects of the TRPV1 antagonists JNJ-38893777 and JNJ-17203212 on trigeminal activation. Expression of the immediate early gene c-fos was measured following intracisternal application of inflammatory soup. In a second model, CGRP release into the external jugular vein was determined following injection of capsaicin into the carotid artery. Results: Inflammatory up-regulation of c-fos in the trigeminal brain stem complex was dose-dependently and significantly reduced by both TRPV1 antagonists. Capsaicin-induced CGRP release was attenuated by JNJ-38893777 only in higher dosage. JNJ-17203212 was effective in all doses and fully abolished CGRP release in a time and dose-dependent manner. Conclusion: Our results describe two TRPV1 antagonists that are effective in two in vivo models of migraine. These results suggest that TRPV1 may play a role in the pathophysiological mechanisms, which are relevant to migraine. [ABSTRACT FROM AUTHOR]

Objective: Pro-inflammatory cytokines like Interleukin-1 beta (IL-1β) have been implicated in the pathophysiology of migraine and inflammatory pain. The trigeminal ganglion and calcitonin gene-related peptide (CGRP) are crucial components in the pathophysiology of primary headaches. 5-HT1B/D receptor agonists, which reduce CGRP release, and cyclooxygenase (COX) inhibitors can abort trigeminally mediated pain. However, the cellular source of COX and the interplay between COX and CGRP within the trigeminal ganglion have not been clearly identified. Methods and Results: 1. We used primary cultured rat trigeminal ganglia cells to assess whether IL-1β can induce the expression of COX-2 and which cells express COX-2. Stimulation with IL-1β caused a dose and time dependent induction of COX-2 but not COX-1 mRNA. Immunohistochemistry revealed expression of COX-2 protein in neuronal and glial cells. 2. Functional significance was demonstrated by prostaglandin E2 (PGE2) release 4 hours after stimulation with IL-1β, which could be aborted by a selective COX-2 (parecoxib) and a non-selective COX-inhibitor (indomethacin). 3. Induction of CGRP release, indicating functional neuronal activation, was seen 1 hour after PGE2 and 24 hours after IL-1β stimulation. Immunohistochemistry showed trigeminal neurons as the source of CGRP. IL-1β induced CGRP release was blocked by parecoxib and indomethacin, but the 5-HT1B/D receptor agonist sumatriptan had no effect. Conclusion: We identified a COX-2 dependent pathway of cytokine induced CGRP release in trigeminal ganglia neurons that is not affected by 5-HT1B/D receptor activation. Activation of neuronal and glial cells in the trigeminal ganglion by IL-β leads to an elevated expression of COX-2 in these cells. Newly synthesized PGE2 (by COX-2) in turn activates trigeminal neurons to release CGRP. These findings support a glia-neuron interaction in the trigeminal ganglion and demonstrate a sequential link between COX-2 and CGRP. The results could help to explain the mechanism of action of COX-2 inhibitors in migraine. [ABSTRACT FROM AUTHOR]