Local Gene Expression Changes after UV-Irradiation of Human Skin

UV-irradiation is a well-known translational pain model inducing local inflammation and primary hyperalgesia. The mediators and receptor proteins specifically contributing to mechanical or heat hyperalgesia are still unclear. Therefore, we irradiated buttock skin of humans (n = 16) with 5-fold MED of UV-C and assessed the time course of hyperalgesia and axon reflex erythema. In parallel, we took skin biopsies at 3, 6 and 24 h after UVC irradiation and assessed gene expression levels (RT-PCR ) of neurotrophins (e.g. NGF, BDNF, GDNF), ion channels (e.g. NaV1.7, TRPV1), inflammatory mediators (e.g. CCL-2, CCL-3) and enzymes (e.g. PGES, COX2). Hyperalgesia to mechanical impact (12 m/s) and heat (48°C) stimuli was significant at 6 h (p<0.05 and p<0.01) and 24 h (p<0.005 and p<0.01) after irradiation. Axon reflex erythema upon mechanical and thermal stimuli was significantly increased 3 h after irradiation and particularly strong at 6 h. A significant modulation of 9 genes was found post UV-C irradiation, including NGF (3, 6, 24 h), TrkA (6, 24 h), artemin, bradykinin-1 receptor, COX-2, CCL-2 and CCL-3 (3 and 6 h each). A significant down-regulation was observed for TRPV1 and iNOS (6, 24 h). Individual one-to-one correlation analysis of hyperalgesia and gene expression revealed that changes of Nav1.7 (SCN9A) mRNA levels at 6 and 24 h correlated to the intensity of mechanical hyperalgesia recorded at 24 h post UV-irradiation (Pearson r: 0.57, p<0.04 and r: 0.82, p<0.001). Expression of COX-2 and mPGES at 6 h correlated to the intensity of heat-induced erythema 24 h post UV (r: 0.57, p<0.05 for COX-2 and r: 0.83, p<0.001 for PGES). The individual correlation analyses of functional readouts (erythema and pain response) with local expression changes provided evidence for a potential role of Nav1.7 in mechanical hyperalgesia

Tetrahydrocannabinol (Delta 9-THC) Treatment in Chronic Central Neuropathic Pain and Fibromyalgia Patients: Results of a Multicenter Survey

Central neuropathic pain is difficult to treat, but delta 9-Tetrahydrocannabinol (delta 9-THC) may be a promising therapeutic agent. We administered in 172 patients on average 7.5 mg delta 9-THC over 7 months. Of these, 48 patients prematurely withdrew due to side effects, insufficient analgesia, or expense of therapy. Thus, 124 patients were assessed retrospectively in a multicenter telephone survey. Reported changes in pain intensity, recorded on a numeric rating scale (NRS), Pain Disability Index (PDI), Medical Outcomes Short-Form (SF-12), Quality of Life Impairment by Pain (QLIP), Hospital Anxiety Depression Scale (HADS), and amount of concomitant pain medication were recorded. Psychometric parameters (PDI, SF-12, QLIP, HADS) and pain intensity improved significantly during delta 9-THC treatment. Opioid doses were reduced and patients perceived THC therapy as effective with tolerable side effects. About 25% of the patients, however, did not tolerate the treatment. Therapy success and tolerance can be assessed by a transient delta 9-THC titration and its maintained administration for several weeks. The present survey demonstrates its ameliorating potential for the treatment of chronic pain in central neuropathy and fibromyalgia. A supplemental delta 9-THC treatment as part of a broader pain management plan therefore may represent a promising coanalgesic therapeutic option

Sphingosine-1-phosphate-induced nociceptor excitation and ongoing pain behavior in mice and humans is largely mediated by S1P3 receptor

The biolipid sphingosine-1-phosphate (S1P) is an essential modulator of innate immunity, cell migration, and wound healing. It is released locally upon acute tissue injury from endothelial cells and activated thrombocytes and, therefore, may give rise to acute post-traumatic pain sensation via a yet elusive molecular mechanism. We have used an interdisciplinary approach to address this question, and we find that intradermal injection of S1P induced significant licking and flinching behavior in wild-type mice and a dose-dependent flare reaction in human skin as a sign of acute activation of nociceptive nerve terminals. Notably, S1P evoked a small excitatory ionic current that resulted in nociceptor depolarization and action potential firing. This ionic current was preserved in “cation-free” solution and blocked by the nonspecific Cl− channel inhibitor niflumic acid and by preincubation with the G-protein inhibitor GDP-β-S. Notably, S1P3 receptor was detected in virtually all neurons in human and mouse DRG. In line with this finding, S1P-induced neuronal responses and spontaneous pain behavior in vivo were substantially reduced in S1P3−/− mice, whereas in control S1P1 floxed (S1P1fl/fl) mice and mice with a nociceptor-specific deletion of S1P1−/− receptor (SNS-S1P1−/−), neither the S1P-induced responses in vitro nor the S1P-evoked pain-like behavior was altered. Therefore, these findings indicate that S1P evokes significant nociception via G-protein-dependent activation of an excitatory Cl− conductance that is largely mediated by S1P3 receptors present in nociceptors, and point to these receptors as valuable therapeutic targets for post-traumatic pain.The authors thank K. Braun, T. Martha, and M. Doblander for expert technical assistance. This work was supported by la Generalitat Valenciana and the Ministerio de Economia y Competitividad (A.V.F.M.), the Australian National Health and Medical Research Council Project Grant 535055 to R.V.H., the Intramural Research Programs of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases to R.L.P., and the Austrian Research Funding Agency FWF Project Grants P20562, P25345, and SPIN to M.K

Effects of prolonged and acute muscle pain on the force control strategy during isometric contractions

Musculoskeletal pain is associated with multiple adaptions in movement control. This study aimed to determine whether changes in movement control acquired during acute pain are maintained over days of pain exposure. On day 0, the extensor carpi radialis brevis muscle of healthy participants was injected with nerve growth factor (NGF) to induce persistent movement-evoked pain (n\ua0=\ua013) or isotonic saline as a control (n\ua0=\ua013). On day 2, short-lasting pain was induced by injection of hypertonic saline into extensor carpi radialis brevis muscles of all participants. Three-dimensional force components were recorded during submaximal isometric wrist extensions on day 0, day 4, and before, during, and after saline-induced pain on day 2. Standard deviation (variation of task-related force) and total excursion of center of pressure (variation of force direction) were assessed. Maximal movement-evoked pain was 3.3\ua0±\ua0.4 (0–10 numeric scale) in the NGF-group on day 2 whereas maximum saline-induced pain was 6.8\ua0±\ua0.3\ua0cm (10-cm visual analog scale). The difference in centroid position of force direction relative to day 0 was greater in the NGF group than in the control group (P\ua

Cutaneous nociception and neurogenic inflammation evoked by PACAP38 and VIP

Pituitary adenylate cyclase-activating peptide-38 (PACAP38) and vasoactive intestinal peptide (VIP) belong to the same secretin–glucagon superfamily and are present in nerve fibers in dura and skin. Using a model of acute cutaneous pain we explored differences in pain perception and vasomotor responses between PACAP38 and VIP in 16 healthy volunteers in a double-blind, placebo-controlled, crossover study. All participants received intradermal injections of 200 pmol PACAP38, 200 pmol VIP and placebo into the volar forearm. Measurements included pain intensity on a visual analog scale (VAS), blood flow by laser Doppler flowmetry, visual flare and wheal. Pain intensities after PACAP38 and VIP were mild and limited to a short time of about 100 s after injection. The area under the VAS-time curve was larger following PACAP38 (P = 0.004) and VIP (P = 0.01) compared to placebo. We found no statistical difference in pain perception between PACAP38 and VIP. Skin blood flow increase, flare and wheal were larger after both PACAP38 (P = 0.011) and VIP (P = 0.001) compared to placebo. VIP induced a considerably larger increase in skin blood flow, flare and wheal than PACAP38 (P = 0.002). In conclusion, we found that peripheral nociceptive cutaneous responses elicited by PACAP38 and VIP are similar in healthy volunteers. This suggests that acute pain and vasomotor responses following intradermal injections of PACAP38 and VIP are primarily mediated by VPAC receptors

Protest -- Pitching -- Crossover Dreaming: Californian Latino/a Film Festivals and Their Promotion of Latinidad

Rukwied A. Protest -- Pitching -- Crossover Dreaming: Californian Latino/a Film Festivals and Their Promotion of Latinidad. Bielefeld: Universität Bielefeld; 2021.My dissertation investigates the manifold ways Latino/a film festivals based in three Californian metropolitan regions – the San Diego-Tijuana transborder region; Greater Los Angeles; and the San Francisco-Bay Area – all have promoted their distinctive visions and identities, latinidad, as articulated by way of their festival practices and their appeal to imagined communities. The title – “Protest, Pitching, Crossover Dreaming” – was inspired by my main argument: These film festivals are activist, special interest events whose respective missions and practices are intricately tied to each festival’s politics of identity, place/location, and commerce. Not least of all, this is also reflected by their respective stakeholder constellations (e.g., organizers, filmmakers, sponsors, audiences). In fact, each festival’s take on latinidad is shown to be a constant negotiation between its original mission and its ever-evolving “environment” (Rüling 2009) and here, their self-imposed obligation to accommodate the changing needs and demands of their target communities and their need to reckon with sociopolitical, technological and economic factors. In a nutshell, my thesis not only shines a light on the challenges and successes associated with providing an arena for Latinx film productions, talent and subjectivities; what is more, it also attests to the ongoing necessity to disseminate stories that mirror U.S. society in ALL its complexity and diversity. The theoretical and historical chapters navigate a wide world of scholarship ranging from traditional and contemporary media, film, film festival and performance studies to cultural, social and specifically ethnic – Chicano/a/x, Raza and Latino/a/x – studies. The theoretical chapter briefly traces some of the cultural, communal and commercial roots of the festive paradigms of old and then provides a more exhaustive overview of a number of traditional and more current issues in conjunction with and beyond the film festival’s original role – upon its emergence in the early/mid-20th century – as cultural and economic arena. This chapter also takes into account the exceptional situation of U.S. based film festivals: their overall belatedness, which can be seen both as a result of the U.S.’s historical lack of a support infrastructure provided by the state, and Hollywood’s long-time lack of interest (pre-Sundance, pre-indiewood) in national film festivals due to its eye on international markets. The next chapter jump-cuts to a discussion of Latino/a film activism, including its transnational lineage to Latin American Tercer Cine, and the development of U.S. Latino/a identified cinema – its arenas of exhibition as well as its ongoing struggle for visibility and opportunities. The analytical part further explores, critiques and substantiates the claims and findings articulated in the previous chapters, drawing on my fieldwork activities (2008- 2012), in the course of which I conducted numerous qualitative interviews, as well as my assessment of print and online promotional materials published by the festivals under scrutiny in the analytical chapters. My focus here is on the San Diego Latino Film Festival (since 1994), L.A. based Reel Rasquache Arts and Film Festival (2004-14), and the Bay’s historical festivals – both of Cine Acción (Women of the Americas, 1988, and ¡Cine Latino!, 1993-2004) and the International Latino Film Festival San Francisco (1997-2008) – and finally, today’s San Francisco Latino Film Festival, organized by Cine+Mas (since 2009). The conclusion wraps up my findings