Two TRPV1 receptor antagonists are effective in two different experimental models of migraine

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

Stress-induced analgesia in patients with chronic musculoskeletal pain and healthy controls

Introduction: Individuals with chronic musculoskeletal pain show impairments in their pain-modulatory capacity. Stress-induced analgesia (SIA) is a paradigm of endogenous pain inhibition mainly tested in animals. It has not been tested in patients with chronic pain despite the important role of stress in pain modulation and the chronicity process. Methods: SIA was tested in 22 patients with chronic musculoskeletal pain and 18 healthy participants matched for age and gender. Pain thresholds, pain tolerance and suprathreshold pain sensitivity were examined before and after a cognitive stressor. Additionally, chronic stress levels, pain catastrophizing and pain characteristics were assessed as potential modulating factors. Results: Patients with chronic musculoskeletal pain compared to healthy controls showed significantly impaired SIA (F(1,37)=5.63, p=.02) for pain thresholds, but not pain tolerance (F(1,37)=0.05, p=.83) and stress-induced hyperalgesia (SIH) to suprathreshold pain ratings (F(1,37)=7.76, p=.008). Patients (r(22)=-0.50, p=.05) but not controls (r(18)=-0.39, p=.13) with high catastrophizing had low SIA as assessed by pain thresholds. In controls suprathreshold pain ratings were significantly positively correlated with catastrophizing (r(18)=0.57, p=.03) and life-time stress exposure (r(18)=0.54, p=.03). In patients neither catastrophizing (r(22)=0.21, p=.34) nor stress exposure (r(22)=0.34, p=.34) were associated with suprathreshold SIH. Discussion: Our data suggest impairments of SIA and SIH in patients with chronic musculoskeletal pain. Catastrophizing was associated with deficient SIA in the patients and higher pain ratings in controls. High life time stress also increased pain ratings in the controls

Blick zurück nach vorn. Architektur und Stadtplanung in der DDR

Der aktualisierten Sichtweise auf einen widerspruchsvollen Architekturprozess war im November 2014 in Berlin eine Tagung des Arbeitskreises „Kunst in der DDR“ gewidmet. Aus den dort vorgestellten Beiträgen setzt sich die vorliegende Sammlung von sieben Aufsätzen zusammen. Es ist nicht ungewöhnlich, das Bauschaffen in einen umfassenderen Kunstdiskurs einzubetten, da es nicht zuletzt um Ausdruckswerte und die kreative Leistung von Individuen geht, doch stellen sich hier Fragen der Ökonomie, der Technik und des Gebrauchswerts in ganz anderer Dimension

Stratifying patients with peripheral neuropathic pain based on sensory profiles : algorithm and sample size recommendations

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.Peer reviewe

IL-1β Stimulates COX-2 Dependent PGE2 Synthesis and CGRP Release in Rat Trigeminal Ganglia Cells

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 (PGE(2)) 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 PGE(2) 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 PGE(2) (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