Dissociation of μ- and δ-opioid inhibition of glutamatergic synaptic transmission in superficial dorsal horn

<p>Abstract</p> <p>Background</p> <p>There is anatomical and behavioural evidence that μ- and δ-opioid receptors modulate distinct nociceptive modalities within the superficial dorsal horn. The aim of the present study was to examine whether μ- and δ-opioid receptor activation differentially modulates TRP sensitive inputs to neurons within the superficial dorsal horn. To do this, whole cell patch clamp recordings were made from lamina I - II neurons in rat spinal cord slices <it>in vitro </it>to examine the effect of opioids on TRP agonist-enhanced glutamatergic spontaneous miniature excitatory postsynaptic currents (EPSCs).</p> <p>Results</p> <p>Under basal conditions the μ-opioid agonist DAMGO (3 μM) reduced the rate of miniature EPSCs in 68% of neurons, while the δ- and κ-opioid agonists deltorphin-II (300 nM) and U69593 (300 nM) did so in 13 - 17% of neurons tested. The TRP agonists menthol (400 μM) and icilin (100 μM) both produced a Ca²⁺-dependent increase in miniature EPSC rate which was unaffected by the voltage dependent calcium channel (VDCC) blocker Cd²⁺. The proportion of neurons in which deltorphin-II reduced the miniature EPSC rate was enhanced in the presence of icilin (83%), but not menthol (0%). By contrast, the proportion of DAMGO and U69593 responders was unaltered in the presence of menthol (57%, 0%), or icilin (57%, 17%).</p> <p>Conclusions</p> <p>These findings demonstrate that δ-opioid receptor activation selectively inhibits inputs activated by icilin, whereas μ-opioid receptor activation has a more widespread effect on synaptic inputs to neurons in the superficial dorsal horn. These findings suggest that δ-opioids may provide a novel analgesic approach for specific, TRPA1-like mediated pain modalities.</p

Facies architecture, emplacement mechanisms and eruption style of the submarine andesite El Barronal complex, Cabo de Gata, SE Spain

El Barronal complex consists of a succession of andesite lavas and andesite volcaniclastic facies interbedded with carbonate and siliciclastic sedimentary rocks. Carbonate and siliciclastic rocks were deposited in a shallow-marine environment during periods of volcanic quiescence. Lavas consist of an inner coherent core grading outward into hyaloclastite breccia made of dense clasts that in turn grade into hyaloclastite breccia made of vesicular clasts, in massive to layered zones. Volcaniclastic facies contain clasts produced during explosive eruptions and reworked clasts from sources above wave base. Volcaniclastic facies were deposited from cold granular flows with different grain size populations. Stratigraphy and facies architecture at El Barronal suggest that a succession of several discrete eruptive events occurred with a similar cyclic pattern made of an initial explosive phase followed by effusive emplacement of lavas, in turn followed by a period of quiescence of volcanic activity. Hyaloclastic fragmentation of magma took place in the final stages of lava emplacement, allowing only for local disorganization of the jigsaw-fit texture. © 2013 Elsevier B.V.This research has been funded by projects CGL2005-03511/BTE and HI2006-0073Peer Reviewe

The Gamma-Ray Imaging Spectrometer (GRIS): A new balloon-borne experiment for gamma-ray line astronomy

High resolution gamma-ray spectroscopy is a relatively new field that holds great promise for further understanding of high energy astrophysical processes. When the high resolution gamma-ray spectrometer (GRSE) was removed from the GRO payload, a balloon program was initiated to permit continued development and improvement of instrumentation in this field, as well as continued scientific observations. The Gamma-Ray Imaging Spectrometer (GRIS) is one of the experiments selected as part of this program. The instrument contains a number of new and innovative features that are expected to produce a significant improvement in source location accuracy and sensitivity over previous balloon and satellite experiments

Quality of Life and psychopathology in adults who underwent Hematopoietic Stem Cell Transplantation (HSCT) in childhood: a qualitative and quantitative analysis.

Background: Patients who undergo pediatric Hematopoietic Stem Cell Transplantation (HSCT) may experience long-term psychological sequelae and poor Quality of Life (QoL) in adulthood. This study aimed to investigate subjective illness experience, QoL, and psychopathology in young adults who have survived pediatric HSCT. Method: The study involved patients treated with HSCT in the Hematology-Oncology Department between 1984 and 2007. Psychopathology and QoL were investigated using the SCL-90-R and SF-36. Socio-demographic and medical information was also collected. Finally, participants were asked to write a brief composition about their experiences of illness and care. Qualitative analysis of the texts was performed using T-LAB, an instrument for text analysis that allows the user to highlight the occurrences and co-occurrences of lemma. Quantitative analyses were performed using non-parametric tests (Spearman correlations, Kruskal-Wallis and Mann-Whitney tests). Results: Twenty-one patients (9 males) participated in the study. No significant distress was found on the SCL-90 Global Severity Index, but it was found on specific scales. On the SF-36, lower scores were reported on scales referring to bodily pain, general health, and physical and social functioning. All the measures were significantly (p < 0.05) associated with specific socio-demographic and medical variables (gender, type of pathology, type of HSCT, time elapsed between communication of the need to transplant and effective transplantation, and days of hospitalization). With regard to the narrative analyses, males focused on expressions related to the body and medical therapies, while females focused on people they met during treatment, family members, and donors. Low general health and treatment with autologous HSCT were associated with memories about chemotherapy, radiotherapy, and the body parts involved, while high general health was associated with expressions focused on gratitude (V-Test \ub1 1.96). Conclusion: Pediatric HSCT survivors are more likely to experience psychological distress and low QoL in adulthood compared with the general population. These aspects, along with survivors' subjective illness experience, show differences according to specific medical and socio-demographic variables. Studies are needed in order to improve the care and long-term follow-up of these families

Fetal-Perinatal Exposure to Bisphenol-A Affects Quality of Spermatozoa in Adulthood Mouse

Bisphenol-A (BPA) is considered an endocrine disruptor with estrogenic activity. It is described as an environment-polluting industrial chemical whose adverse effects on the male reproductive system depend on the period of exposure (i.e., fetal, prepubertal, or adult life). We exposed male mice to BPA during the fetal-perinatal period (from 10 days post coitum to 31 days post partum) and investigated the impact of this early-life exposure on gamete health in adulthood animals at 78 days of age. Both in control and BPA-exposed mice, viability and motility of spermatozoa, as well as sperm motility acquisition and chromatin condensation of spermatozoa, have been evaluated. Results reveal harmful effect of BPA on viability and motility of sperm cells as well as on chromatin condensation status during epididymal maturation of spermatozoa. In particular, BPA exposure interferes with biochemical mechanism useful to stabilize sperm chromatin condensation, as it interferes with oxidation of thiol groups associated to chromatin

The cannabinoid receptor cb1 stabilizes sperm chromatin condensation status during epididymal transit by promoting disulphide bond formation

The cannabinoid receptor CB1 regulates differentiation of spermatids. We recently characterized spermatozoa from caput epididymis of CB1-knock-out mice and identified a considerable number of sperm cells with chromatin abnormality such as elevated histone content and poorly condensed chromatin. In this paper, we extended our findings and studied the role of CB1 in the epididymal phase of chromatin condensation of spermatozoa by analysis of spermatozoa from caput and cauda epididymis of wild-type and CB1-knock-out mouse in both a homozygous or heterozygous condition. Furthermore, we studied the impact of CB1-gene deletion on histone displacement mechanism by taking into account the hyperacetylation of histone H4 and players of displacement such as Chromodomain Y Like protein (CDYL) and Bromodomain testis-specific protein (BRDT). Our results show that CB1, via local and/or endocrine cell-to-cell signaling, modulates chromatin remodeling mechanisms that orchestrate a nuclear condensation extent of mature spermatozoa. We show that CB1-gene deletion affects the epididymal phase of chromatin condensation by interfering with inter-/intra-protamine disulphide bridges formation, and deranges the efficiency of histone removal by reducing the hyper-acetylation of histone H4. This effect is independent by gene expression of Cdyl and Brdt mRNA. Our results reveal a novel and important role for CB1 in sperm chromatin condensation mechanisms

Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain

Gabapentin is a first-line therapy for neuropathic pain but its mechanisms and sites of action remain uncertain. We investigated gabapentin-induced modulation of neuropathic pain following spinal nerve ligation (SNL) in rats. Intravenous or intrathecal gabapentin reversed evoked mechanical hypersensitivity, produced conditioned place preference (CPP) and dopamine release in the nucleus accumbens (NAc) selectively in SNL rats. Spinal gabapentin also significantly inhibited dorsal horn wide dynamic range (WDR) neuronal responses to a range of evoked stimuli in SNL rats. In contrast, gabapentin microinjected bilaterally into the rostral anterior cingulate cortex (rACC), produced CPP and elicited NAc dopamine release selectively in SNL rats but did not reverse tactile allodynia and had marginal effects on WDR neuronal activity. Moreover, blockade of endogenous opioid signaling in the rACC prevented intravenous gabapentin-induced CPP and NAc dopamine release but failed to block its inhibition of tactile allodynia. Gabapentin therefore can potentially act to produce its pain relieving effects by (a) inhibition of injury-induced spinal neuronal excitability, evoked hypersensitivity and ongoing pain and (b) selective supraspinal modulation of affective qualities of pain, without alteration of reflexive behaviors. Consistent with previous findings of pain relief from non-opioid analgesics, gabapentin requires engagement of rACC endogenous opioid circuits and downstream activation of mesolimbic reward circuits reflected in learned pain motivated behaviors. These findings support the partial separation of sensory and affective dimensions of pain in this experimental model and suggest that modulation of affective-motivational qualities of pain may be the preferential mechanism of gabapentin’s analgesic effects in patients

Characterization of estrogenic activity and site‐specific accumulation of bisphenol‐a in epididymal fat pad: Interfering effects on the endocannabinoid system and temporal progression of germ cells

The objective of this work has been to characterize the estrogenic activity of bisphenol‐A (BPA) and the adverse effects on the endocannabinoid system (ECS) in modulating germ cell progression. Male offspring exposed to BPA during the foetal‐perinatal period at doses below the no‐observed‐adverse‐effect‐level were used to investigate the exposure effects in adulthood. Results showed that BPA accumulates specifically in epididymal fat rather than in abdominal fat and targets testicular expression of 3β‐hydroxysteroid dehydrogenase and cytochrome P450 aromatase, thus promoting sustained increase of estrogens and a decrease of testosterone. The exposure to BPA affects the expression levels of some ECS components, namely type‐1 (CB1) and type‐2 cannabinoid (CB2) receptor and monoacylglycerol‐lipase (MAGL). Furthermore, it affects the temporal progression of germ cells reported to be responsive to ECS and promotes epithelial germ cell exfoliation. In particular, it increases the germ cell content (i.e., spermatogonia while reducing spermatocytes and spermatids), accelerates progression of spermatocytes and spermatids, promotes epithelial detachment of round and condensed spermatids and interferes with expression of cell–cell junction genes (i.e., zonula occcludens protein‐1, vimentin and β‐catenin). Altogether, our study provides evidence that early exposure to BPA produces in adulthood sustained and site‐specific BPA accumulation in epididymal fat, becoming a risk factor for the reproductive endocrine pathways associated to ECS

Comparison between "In-bore" MRI guided prostate biopsy and standard ultrasound guided biopsy in the patient with suspicious prostate cancer: Preliminary results.

OBJECTIVES: To evaluate the detection rate of prostate cancer (PCa) in patients who underwent to "in bore" Magnetic Resonance Imaging -guided prostate (MRI-GB) biopsy compared to the standard transrectal ultrasound guided prostate biopsy (TRUS-GB). MATERIALS AND METHODS: Between January 2017 and March 2015 a cohort of 39 consecutive patients was prospectively enrolled. All the patients underwent an "in-bore" guided MRI prostatic biopsy and subsequently ultrasound-guided standard prostate biopsy. RESULTS: Median age of patients was 65.5 years (SD \ub1 6.6), median total PSA serum level was 6.6 ng/ml (SD \ub1 4.1), median prostate total volume was 51.1 cc (SD \ub1 26.7). Thirty of 39 (76.9%) were biopsy-na\uefve patients while 7/39 (17.9%) had at least one previous negative random TRUS-GB; 2/39 (5.1%) patients were already diagnosed as PCa and were on active surveillance. In 18/39 (53.8%) men Pca was diagnosed; as regards the MRI-GB results related to the PI-RADS score, biopsies of PIRADS 3 lesions were positive in 5/18 cases (27.8%), while the number of positive cases of PI-RADS 4 and 5 lesions was 7/11 (63.6%) and 6/10 (60%)respectively. At the histological examination, 4/39 (10.3%) had a PCa ISUP grade group 1, 11/39 (28.2%) had a ISUP 2, 6/39(15.4%) had a ISUP grade group 3 and 2/39 (5.1%) had a ISUP 4-5. CONCLUSIONS: MRI-GB represents a promising technique that may offer some of advantages compared to standard systematic TRUSGB. Our preliminary experience in MRI-GB resulted safe and feasible and represents a viable procedure for the diagnosis and characterization of PCa

Evaluation of low doses BPA-induced perturbation of glycemia by toxicogen-omics points to a primary role of pancreatic islets and to the mechanism of toxicity

Epidemiologic and experimental studies have associated changes of blood glucose homeostasis to Bisphenol A (BPA) exposure. We took a toxicogenomic approach to investigate the mechanisms of low-dose (1 ? 10-9 M) BPA toxicity in ex vivo cultures of primary murine pancreatic islets and hepatocytes. Twenty-nine inhibited genes were identified in islets and none in exposed hepatocytes. Although their expression was slightly altered, their impaired cellular level, as a whole, resulted in specific phenotypic changes. Damage of mitochondrial function and metabolism, as predicted by bioinformatics analyses, was observed: BPA exposure led to a time-dependent decrease in mitochondrial membrane potential, to an increase of ROS cellular levels and, finally, to an induction of apoptosis, attributable to the bigger Bax/Bcl-2 ratio owing to activation of NF-[[ampi]]kappa;B pathway. Our data suggest a multifactorial mechanism for BPA toxicity in pancreatic islets with emphasis to mitochondria dysfunction and NF-[[ampi]]kappa;B activation. Finally, we assessed in vitro the viability of BPA-treated islets in stressing condition, as exposure to high glucose, evidencing a reduced ability of the exposed islets to respond to further damages. The result was confirmed in vivo evaluating the reduction of glycemia in hyperglycemic mice transplanted with control and BPA-treated pancreatic islets. The reported findings identify the pancreatic islet as the main target of BPA toxicity in impairing the glycemia. They suggest that the BPA exposure can weaken the response of the pancreatic islets to damages. The last observation could represent a broader concept whose consideration should lead to the development of experimental plans better reproducing the multiple exposure conditions