Successful radical resection of a leiomyosarcoma of the pulmonary trunk

AbstractJ Thorac Cardiovasc Surg 2001;122:1039-4

Antidepressants Inhibit P2X4 Receptor Function: a Possible Involvement in Neuropathic Pain Relief

BACKGROUND: Neuropathic pain is characterized by pain hypersensitivity to innocuous stimuli (tactile allodynia) that is nearly always resistant to known treatments such as non-steroidal anti-inflammatory drugs or even opioids. It has been reported that some antidepressants are effective for treating neuropathic pain. However, the underlying molecular mechanisms are not well understood. We have recently demonstrated that blocking P2X(4 )receptors in the spinal cord reverses tactile allodynia after peripheral nerve injury in rats, implying that P2X(4 )receptors are a key molecule in neuropathic pain. We investigated a possible role of antidepressants as inhibitors of P2X(4 )receptors and analysed their analgesic mechanism using an animal model of neuropathic pain. RESULTS: Antidepressants strongly inhibited ATP-mediated Ca(2+ )responses in P2X(4 )receptor-expressing 1321N1 cells, which are known to have no endogenous ATP receptors. Paroxetine exhibited the most powerful inhibition of calcium influx via rat and human P2X(4 )receptors, with IC(50 )values of 2.45 μM and 1.87 μM, respectively. Intrathecal administration of paroxetine produced a striking antiallodynic effect in an animal model of neuropathic pain. Co-administration of WAY100635, ketanserin or ondansetron with paroxetine induced no significant change in the antiallodynic effect of paroxetine. Furthermore, the antiallodynic effect of paroxetine was observed even in rats that had received intrathecal pretreatment with 5,7-dihydroxytryptamine, which dramatically depletes spinal 5-hydroxytryptamine. CONCLUSION: These results suggest that paroxetine acts as a potent analgesic in the spinal cord via a mechanism independent of its inhibitory effect on serotonin transporters. Powerful inhibition on P2X(4 )receptors may underlie the analgesic effect of paroxetine, and it is possible that some antidepressants clinically used in patients with neuropathic pain show antiallodynic effects, at least in part via their inhibitory effects on P2X(4 )receptors

Behavioral phenotypes of mice lacking purinergic P2X4 receptors in acute and chronic pain assays

A growing body of evidence indicates that P2X receptors (P2XRs), a family of ligand-gated cation channels activated by extracellular ATP, play an important role in pain signaling. In contrast to the role of the P2X3R subtype that has been extensively studied, the precise roles of others among the seven P2XR subtypes (P2X1R-P2X7R) remain to be determined because of a lack of sufficiently powerful tools to specifically block P2XR signaling in vivo. In the present study, we investigated the behavioral phenotypes of a line of mice in which the p2rx4 gene was disrupted in a series of acute and chronic pain assays. While p2rx4-/- mice showed no major defects in pain responses evoked by acute noxious stimuli and local tissue damage or in motor function as compared with wild-type mice, these mice displayed reduced pain responses in two models of chronic pain (inflammatory and neuropathic pain). In a model of chronic inflammatory pain developed by intraplantar injection of complete Freund's adjuvant (CFA), p2rx4-/- mice exhibited attenuations of pain hypersensitivity to innocuous mechanical stimuli (tactile allodynia) and also of the CFA-induced swelling of the hindpaw. A most striking phenotype was observed in a test of neuropathic pain: tactile allodynia caused by an injury to spinal nerve was markedly blunted in p2rx4-/- mice. By contrast, pain hypersensitivity to a cold stimulus (cold allodynia) after the injury was comparable in wild-type and p2rx4-/- mice. Together, these findings reveal a predominant contribution of P2X4R to nerve injury-induced tactile allodynia and, to the lesser extent, peripheral inflammation. Loss of P2X4R produced no defects in acute physiological pain or tissue damaged-induced pain, highlighting the possibility of a therapeutic benefit of blocking P2X4R in the treatment of chronic pain, especially tactile allodynia after nerve injury

Reduced spinal microglial activation and neuropathic pain after nerve injury in mice lacking all three nitric oxide synthases

<p>Abstract</p> <p>Background</p> <p>Several studies have investigated the involvement of nitric oxide (NO) in acute and chronic pain using mice lacking a single NO synthase (NOS) gene among the three isoforms: neuronal (nNOS), inducible (iNOS) and endothelial (eNOS). However, the precise role of NOS/NO in pain states remains to be determined owing to the substantial compensatory interactions among the NOS isoforms. Therefore, in this study, we used mice lacking all three NOS genes (<it>n/i/eNOS^-/-</it>mice) and investigated the behavioral phenotypes in a series of acute and chronic pain assays.</p> <p>Results</p> <p>In a model of tissue injury-induced pain, evoked by intraplantar injection of formalin, both <it>iNOS^-/-</it>and <it>n/i/eNOS^-/-</it>mice exhibited attenuations of pain behaviors in the second phase compared with that in wild-type mice. In a model of neuropathic pain, nerve injury-induced behavioral and cellular responses (tactile allodynia, spinal microglial activation and Src-family kinase phosphorylation) were reduced in <it>n/i/eNOS^-/-</it>but not <it>iNOS^-/-</it>mice. Tactile allodynia after nerve injury was improved by acute pharmacological inhibition of all NOSs and nNOS. Furthermore, in MG-5 cells (a microglial cell-line), interferon-γ enhanced NOSs and Mac-1 mRNA expression, and the Mac-1 mRNA increase was suppressed by L-NAME co-treatment. Conversely, the NO donor, sodium nitroprusside, markedly increased mRNA expression of Mac-1, interleukin-6, toll-like receptor 4 and P2X4 receptor.</p> <p>Conclusions</p> <p>Our results provide evidence that the NOS/NO pathway contributes to behavioral pain responses evoked by tissue injury and nerve injury. In particular, nNOS may be important for spinal microglial activation and tactile allodynia after nerve injury.</p

Association between reduced serum BDNF levels and insomnia with short sleep duration among female hospital nurses

Objective: Previous studies have suggested that brain-derived neurotrophic factor (BDNF) is associated with sleep regulation in humans. However, its relationship with self-reported sleep problems has not been clarified. The aim of the present study was to examine the association between serum BDNF levels and sleep problems among hospital nurses. Methods: Participants were enrolled from among nurses working at a general hospital in Tokyo, Japan. Data from 577 women (age: 35.45 ± 10.90 years) were analyzed. This cross-sectional survey was conducted from November to December 2015. Serum BDNF concentrations were evaluated. Participants completed a self-reported questionnaire on sleep including the presence or absence of insomnia symptoms (ie, difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS), and early morning awakening [EMA]), and sleep duration. Insomnia with short sleep duration (ISS) was defined as: DIS, or DMS, or EMA; and <6 h sleep duration. Results: Among 577 participants, 21.3% reported insomnia, 41.4% slept less than 6 h, and finally 12.5% suffered from ISS. Serum BDNF levels were significantly lower in subjects with ISS than in those without ISS. The serum BDNF levels in insomniacs were significantly lower than in non-insomniacs for short sleep duration (<6 h), while serum BDNF levels did not differ between insomniacs and non-insomniacs for normal sleep duration (≥6 h). Conclusion: This is the first documented study to indicate that ISS is associated with reduced serum BDNF levels. These results may lead to clarification of the underlying pathophysiological relationship between BDNF and poor sleep

Observation of domain wall bimerons in chiral magnets

Topological defects embedded in or combined with domain walls have been proposed in various systems, some of which are referred to as domain wall skyrmions or domain wall bimerons. However, the experimental observation of such topological defects remains an ongoing challenge. Here, using Lorentz transmission electron microscopy, we report the experimental discovery of domain wall bimerons in chiral magnet Co-Zn-Mn(110) thin films. By applying a magnetic field, multidomain structures develop, and simultaneously, chained and isolated bimerons arise as the localized state between the domains with the opposite in-plane components of net magnetization. The multidomain formation is attributed to magnetic anisotropy and dipolar interaction, and domain wall bimerons are stabilized by the Dzyaloshinskii-Moriya interaction. In addition, micromagnetic simulations show that domain wall bimerons appear for a wide range of conditions in chiral magnets with cubic magnetic anisotropy. Our results promote further study in various fields of physics.Comment: 30 pages, 10 figures (including Supplementary Materials

Purinergic P2Y(6) receptors heterodimerize with angiotensin AT1 receptors to promote angiotensin II-induced hypertension

The angiotensin (Ang) type 1 receptor (AT1R) promotes functional and structural integrity of the arterial wall to contribute to vascular homeostasis, but this receptor also promotes hypertension. In our investigation of how Ang II signals are converted by the AT1R from physiological to pathological outputs, we found that the purinergic P2Y6 receptor (P2Y6R), an inflammation-inducible G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptor (GPCR), promoted Ang II–induced hypertension in mice. In mice, deletion of P2Y6R attenuated Ang II–induced increase in blood pressure, vascular remodeling, oxidative stress, and endothelial dysfunction. AT1R and P2Y6R formed stable heterodimers, which enhanced G protein–dependent vascular hypertrophy but reduced β-arrestin–dependent AT1R internalization. Pharmacological disruption of AT1R-P2Y6R heterodimers by the P2Y6R antagonist MRS2578 suppressed Ang II–induced hypertension in mice. Furthermore, P2Y6R abundance increased with age in vascular smooth muscle cells. The increased abundance of P2Y6R converted AT1R-stimulated signaling in vascular smooth muscle cells from β-arrestin–dependent proliferation to G protein–dependent hypertrophy. These results suggest that increased formation of AT1R-P2Y6R heterodimers with age may increase the likelihood of hypertension induced by Ang II