Activation of Transient Receptor Potential Vanilloid 1 Is Involved in Both Pain and Tumor Growth in a Mouse Model of Cancer Pain.

Activation of calcitonin gene-related peptide (CGRP)-positive sensory neurons in the tumor microenvironment has been shown to be involved in tumor growth. However, how CGRP-positive sensory neurons are activated requires elucidation. In this study, we focused on transient receptor potential vanilloid 1 (TRPV1) and examined the contribution of TRPV1 to tumor growth and cancer pain in a mouse cancer model in which Lewis lung carcinoma was subcutaneously inoculated in the left plantar region. Tumor inoculation gradually increased the volumes of the hind paws of wild type (WT) mice over time, but those of both αCGRP knockout mice and TRPV1 knockout mice were significantly smaller than those of WT mice after tumor inoculation. Both TRPV1 and CGRP are therefore suggested to be involved in tumor growth. In an immunohistochemical study, the percentage of phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB)-positive profiles in CGRP-positive dorsal root ganglion (DRG) neurons in WT mice was significantly increased after tumor inoculation. The percentage of p-CREB-positive profiles in CGRP-positive DRG neurons in TRPV1 knockout mice was also increased after tumor inoculation, but was significantly lower than that in WT mice, indicating the contribution of TRPV1 to activation of CGRP-positive DRG neurons. Cancer pain in TRPV1 knockout mice was significantly lower than that in WT mice. In conclusion, TRPV1 is involved in both tumor growth and cancer pain, potentially leading to a novel strategy for the treatment of cancer pain and cancer development. Cancer pain is also suggested to facilitate tumor growth.

A Case of Decreased Amplitude in Motor Evoked Potentials Under Remimazolam Anesthesia.

Remimazolam is a newly developed benzodiazepine derivative. Although one case report on the use of remimazolam for motor evoked potential (MEP) monitoring has been reported, there has been no report of changes in the MEP response under remimazolam anesthesia, which is associated with impairment of the corticospinal motor track. This is a case of a 54-year-old woman who was diagnosed with an extradural extramedullary tumor. The patient reported being allergic to chicken eggs. We used remimazolam instead of propofol for anesthesia management. During tumor resection, the amplitudes of MEP responses at the left quadriceps femoris, left tibialis anterior, and left abductor hallucis muscle decreased. The surgery was scaled down and the tumor was removed in a reduced size. The patient had muscle weakness immediately after surgery but eventually recovered. In this case, we could detect changes in MEP response under remimazolam anesthesia, which suggested impairment of the motor tracts during surgery.

Compton Scattering of Hermite Gaussian Wave γ Ray.

One of candidates for the generation mechanism of high linearly polarized γ rays in γ-ray bursts is synchrotron radiations from high energy electrons under strong magnetic fields. If this scenario is true, Hermite Gaussian (HG) wave photons, which are one of high-order Gaussian modes, are also generated by high-order harmonic radiations in strong magnetic fields. The HG wave γ rays propagating along the z-direction have quantum numbers of nodes of nx and ny in the x- and y-directions, respectively. We calculate the differential cross sections for Compton scattering of photons described by HG wave function in the framework of relativistic quantum mechanics. The results indicate that it is possible to identify the HG wave photon and its quantum numbers nx and ny and by measuring the azimuthal angle dependence of differential cross section or the energy spectra of the scattered photon as a function of the azimuthal angle.

Transcription factor Sp4 is required for hyperalgesic state persistence.

Understanding how painful hypersensitive states develop and persist beyond the initial hours to days is critically important in the effort to devise strategies to prevent and/or reverse chronic painful states. Changes in nociceptor transcription can alter the abundance of nociceptive signaling elements, resulting in longer-term change in nociceptor phenotype. As a result, sensitized nociceptive signaling can be further amplified and nocifensive behaviors sustained for weeks to months. Building on our previous finding that transcription factor Sp4 positively regulates the expression of the pain transducing channel TRPV1 in Dorsal Root Ganglion (DRG) neurons, we sought to determine if Sp4 serves a broader role in the development and persistence of hypersensitive states in mice. We observed that more than 90% of Sp4 staining DRG neurons were small to medium sized, primarily unmyelinated (NF200 neg) and the majority co-expressed nociceptor markers TRPV1 and/or isolectin B4 (IB4). Genetically modified mice (Sp4+/-) with a 50% reduction of Sp4 showed a reduction in DRG TRPV1 mRNA and neuronal responses to the TRPV1 agonist-capsaicin. Importantly, Sp4+/- mice failed to develop persistent inflammatory thermal hyperalgesia, showing a reversal to control values after 6 hours. Despite a reversal of inflammatory thermal hyperalgesia, there was no difference in CFA-induced hindpaw swelling between CFA Sp4+/- and CFA wild type mice. Similarly, Sp4+/- mice failed to develop persistent mechanical hypersensitivity to hind-paw injection of NGF. Although Sp4+/- mice developed hypersensitivity to traumatic nerve injury, Sp4+/- mice failed to develop persistent cold or mechanical hypersensitivity to the platinum-based chemotherapeutic agent oxaliplatin, a non-traumatic model of neuropathic pain. Overall, Sp4+/- mice displayed a remarkable ability to reverse the development of multiple models of persistent inflammatory and neuropathic hypersensitivity. This suggests that Sp4 functions as a critical control point for a network of genes that conspire in the persistence of painful hypersensitive states.

Compton Scattering of γ-Ray Vortex with Laguerre Gaussian Wave Function.

In this work, we report calculation for Compton scattering of a γ-ray vortex with a wave function of Laguerre Gaussian on an electron in the framework of the relativistic quantum mechanics. We consider the coincidence measurement of the scattered photon and the scattered electron from each Compton scattering. The momentum of the scattered photon distributes outside of the reaction plane determined by the incident photon and the scattered electron, and the energy of the scattered photon also distributes, when the scattered angle of the electron is simultaneously measured. These distributions depend on the angular momentum and the node number of the Laguerre Gaussian function of the incident photon. Thus, the coincident measurement for Compton scattering is useful to identify the nature of the vortex photon wave function.

Comparison of catheter-over-needle and catheter-through-needle on leakage from the catheter insertion site during continuous femoral nerve block.

The aim of this study was to compare the incidences of leakage from the catheter insertion site during continuous femoral nerve block when using the catheter-through-needle, Contiplex Touhy™ (CT) and the newly developed catheter-over-needle, Contiplex C™ (CC). Forty adult patients who were scheduled to undergo continuous femoral nerve block for pain control following knee surgery were enrolled and were randomly assigned to a CT group or a CC group. After finishing surgery, a catheter for continuous femoral nerve block was placed using ultrasound. A catheter was advanced along the femoral nerve 5-6 cm beyond the needle tip. Then 0.25% levobupivacaine was continuously administered at a rate of 5 ml/h until 9:00 am on postoperative day 1. The incidence of leakage of the local anesthetic from the insertion site in the CT group was significantly higher than that in the CC group. In the CT group, leakage from the catheter insertion site was observed in 11 of 20 patients during the observation period. On the other hand, none of the patients in the CC group showed leakage. Contiplex C™ is more effective than Contiplex Touphy™ for prevention of leakage of local anesthetics from the insertion site during continuous femoral nerve block.

Neuroprotective effects of a novel water-soluble poly(ADP-ribose) polymerase-1 inhibitor, MP-124, in in vitro and in vivo models of cerebral ischemia.

Cerebral ischemia induces excessive activation of poly(ADP-ribose) polymerase-1 (PARP-1), leading to neuronal cell death and the development of post-ischemic dysfunction. Blockade of PARP-related signals during cerebral ischemia has become a focus of interest as a new therapeutic approach for acute stroke treatment. The purpose of the present study was to examine the pharmacological profiles of MP-124, a novel water-soluble PARP-1 inhibitor, and its neuroprotective effects on ischemic injury in vitro and in vivo. MP-124 demonstrated competitive inhibition of the PARP-1 activity of human recombinant PARP-1 enzyme (Ki=16.5nmol/L). In P388D(1) cells, MP-124 inhibited the LDH leakage induced by H(2)O(2) in a concentration-dependent manner. (IC(50)=20.8nmol/L). In rat primary cortical neurons, MP-124 also inhibited the NAD depletion and polymerized ADP-ribose formation induced by H(2)O(2) exposure. Moreover, we investigated the neuroprotective effects of MP-124 in rat permanent and transient stroke models. In the rat permanent middle cerebral artery occlusion (MCAO) model, MP-124 was administered intravenously for 24h from 5min after the onset of MCAO. MP-124 (1, 3 and 10mg/kg/h) significantly inhibited the cerebral infarction in a dose-dependent manner (18, 42 and 48%). In rat transient MCAO model, MP-124 was administered intravenously from 30min after the onset of MCAO. MP-124 (3 and 10mg/kg/h) significantly reduced the infarct volume (53% and 50%). The present findings suggest that MP-124 acts as a potent neuroprotective agent in focal ischemia and its actions can be attributed to a reduction in NAD depletion and PAR formation.

Angiotensin II type 2 receptor-mediated inhibition of norepinephrine release in isolated rat hearts.

We investigated whether endogenous and exogenous angiotensin II (Ang II) regulates norepinephrine (NE) release from cardiac sympathetic nerves via both Ang II type 2 receptors (AT2Rs) and Ang II type 1 receptors (AT1Rs). Using isolated rat hearts, sympathetic nerves were electrically stimulated. Ang II with PD-123319 (AT2R antagonist) but not Ang II alone produced a significant increase in nerve stimulation-induced NE overflow, which was abolished by the addition of AT1R antagonist losartan. In contrast, NE overflow was markedly decreased by losartan with or without Ang II. This decrease was abolished by the combination with PD-123319, nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (NOARG), icatibant (bradykinin B2 receptor antagonist), or PKSI-527 (kininogenase inhibitor). CGP-42112A (AT2R agonist) suppressed nerve stimulation-induced NE overflow in the same way as the combination of Ang II and losartan, and this suppression was abolished by PD-123319, NOARG, icatibant, or PKSI-527. There were significant increases in NOx (NO2/NO3) contents in coronary effluent under conditions where NE overflow was suppressed. Ang II seems to function as an inhibitory modulator of cardiac noradrenergic neurotransmission via AT2Rs and well-known AT1R-mediated stimulatory actions. The inhibitory mechanism may involve local bradykinin production, its B2 receptor activation, and NO as a downstream effector.