Gz mediates the long-lasting desensitization of brain CB1 receptors and is essential for cross-tolerance with morphine

Abstract Background Although the systemic administration of cannabinoids produces antinociception, their chronic use leads to analgesic tolerance as well as cross-tolerance to morphine. These effects are mediated by cannabinoids binding to peripheral, spinal and supraspinal CB1 and CB2 receptors, making it difficult to determine the relevance of each receptor type to these phenomena. However, in the brain, the CB1 receptors (CB1Rs) are expressed at high levels in neurons, whereas the expression of CB2Rs is marginal. Thus, CB1Rs mediate the effects of smoked cannabis and are also implicated in emotional behaviors. We have analyzed the production of supraspinal analgesia and the development of tolerance at CB1Rs by the direct injection of a series of cannabinoids into the brain. The influence of the activation of CB1Rs on supraspinal analgesia evoked by morphine was also evaluated. Results Intracerebroventricular (icv) administration of cannabinoid receptor agonists, WIN55,212-2, ACEA or methanandamide, generated a dose-dependent analgesia. Notably, a single administration of these compounds brought about profound analgesic tolerance that lasted for more than 14 days. This decrease in the effect of cannabinoid receptor agonists was not mediated by depletion of CB1Rs or the loss of regulated G proteins, but, nevertheless, it was accompanied by reduced morphine analgesia. On the other hand, acute morphine administration produced tolerance that lasted only 3 days and did not affect the CB1R. We found that both neural mu-opioid receptors (MORs) and CB1Rs interact with the HINT1-RGSZ module, thereby regulating pertussis toxin-insensitive Gz proteins. In mice with reduced levels of these Gz proteins, the CB1R agonists produced no such desensitization or morphine cross-tolerance. On the other hand, experimental enhancement of Gz signaling enabled an acute icv administration of morphine to produce a long-lasting tolerance at MORs that persisted for more than 2 weeks, and it also impaired the analgesic effects of cannabinoids. Conclusion In the brain, cannabinoids can produce analgesic tolerance that is not associated with the loss of surface CB1Rs or their uncoupling from regulated transduction. Neural specific Gz proteins are essential mediators of the analgesic effects of supraspinal CB1R agonists and morphine. These Gz proteins are also responsible for the long-term analgesic tolerance produced by single doses of these agonists, as well as for the cross-tolerance between CB1Rs and MORs.</p

Morphine induces endocytosis of neuronal μ-opioid receptors through the sustained transfer of Gα subunits to RGSZ2 proteins

<p>Abstract</p> <p>Background</p> <p>In general, opioids that induce the recycling of μ-opioid receptors (MORs) promote little desensitization, although morphine is one exception to this rule. While morphine fails to provoke significant internalization of MORs in cultured cells, it does stimulate profound desensitization. In contrast, morphine does promote some internalization of MORs in neurons although this does not prevent this opioid from inducing strong antinociceptive tolerance.</p> <p>Results</p> <p>In neurons, morphine stimulates the long-lasting transfer of MOR-activated Gα subunits to proteins of the RGS-R7 and RGS-Rz subfamilies. We investigated the influence of this regulatory process on the capacity of morphine to promote desensitization and its association with MOR recycling in the mature nervous system. In parallel, we also studied the effects of [D-Ala², <it>N</it>-MePhe⁴, Gly-ol⁵] encephalin (DAMGO), a potent inducer of MOR internalization that promotes little tolerance. We observed that the initial exposure to icv morphine caused no significant internalization of MORs but rather, a fraction of the Gα subunits was stably transferred to RGS proteins in a time-dependent manner. As a result, the antinociception produced by a second dose of morphine administered 6 h after the first was weaker. However, this opioid now stimulated the phosphorylation, internalization and recycling of MORs, and further exposure to morphine promoted little tolerance to this moderate antinociception. In contrast, the initial dose of DAMGO stimulated intense phosphorylation and internalization of the MORs associated with a transient transfer of Gα subunits to the RGS proteins, recovering MOR control shortly after the effects of the opioid had ceased. Accordingly, the recycled MORs re-established their association with G proteins and the neurons were rapidly resensitized to DAMGO.</p> <p>Conclusion</p> <p>In the nervous system, morphine induces a strong desensitization before promoting the phosphorylation and recycling of MORs. The long-term sequestering of morphine-activated Gα subunits by certain RGS proteins reduces the responses to this opioid in neurons. This phenomenon probably increases free Gβγ dimers in the receptor environment and leads to GRK phosphorylation and internalization of the MORs. Although, the internalization of the MORs permits the transfer of opioid-activated Gα subunits to the RGSZ2 proteins, it interferes with the stabilization of this regulatory process and recycled MORs recover the control on these Gα subunits and opioid tolerance develops slowly.</p

Spanish version of “Self-Efficacy for Writing Scale” (SEWS)

p. 86-91La autoeficacia es un constructo muy utilizado en Psicología. El presente estudio se centra en el ámbito educativo y, más concretamente, en la adaptación de la “Self-Efficacy for Writing Scale” (SEWS; Bruning, Dempsey, Kauffman, McKim, y Zumbrunn, 2013), desarrollada para me-dir autoeficacia para la escritura. Participaron en el estudio 512 estudiantes (78% mujeres, 22% hombres) de tres universidades españoles distintas. Todos ellos completaron un cuestionario que incluía la versión española de la escala SEWS, además de la Escala de Autoeficacia General y la Escala de Autoeficacia para la Escritura. Los resultados del análisis factorial explora-torio muestran que la prueba mantiene su dimensionalidad, con una va-rianza explicada de 65.86% y tres factores: Ideación (α = .90), Convencio-nes (α = .89), y Autorregulación (α = .90). Las correlaciones con la Escala de Autoeficacia General son elevadas, pero aún más con la Escala de Au-toeficacia para la Escritura, sugiriendo este último dato que se trata del mismo constructo. Asimismo, se encuentra que los hombres muestran ma-yores valores de autoeficacia en la escala SEWS (general) y en dos de sus dimensiones (Ideación y Convenciones). Finalmente, se discuten las impli-caciones de estos resultados, señalándose las principales limitaciones del es-tudio y sugerencias de investigación futuraS

Calmodulin Supports TRPA1 Channel Association with Opioid Receptors and Glutamate NMDA Receptors in the Nervous Tissue

Supplementary Materials: The following are available online at https://www.mdpi.com/1422-006 7/22/1/229/s1, Figure S1: TRPA1 association with MORs in spinal cord in HINT1-/- and 1R-/- mice. Figure S2: The HINT1 protein or 1R does not support the MOR association with the Nt or Ct regions of TRPA1 channels. Figure S3: CaM mediates the TRPA1 Ct association with MOR in the absence of Ca2+. Figure S4: Pharmacological modulation of TRPA1 associations with MORs and glutamate NMDARs. Figure S5: Formalin-induced inflammatory pain alters TRPA1 associations with MORs and NMDARs. Figure S6: TRPA1 associations with opioid receptors and NMDARs in the CCI model of neuropathic pain.We would like to thank Gabriela de Alba and María José López for their excellent technical assistanceTransient receptor potential ankyrin member 1 (TRPA1) belongs to the family of thermo TRP cation channels that detect harmful temperatures, acids and numerous chemical pollutants. TRPA1 is expressed in nervous tissue, where it participates in the genesis of nociceptive signals in response to noxious stimuli and mediates mechanical hyperalgesia and allodynia associated with different neuropathies. The glutamate N-methyl-d-aspartate receptor (NMDAR), which plays a relevant role in allodynia to mechanical stimuli, is connected via histidine triad nucleotide-binding protein 1 (HINT1) and type 1 sigma receptor (σ1R) to mu-opioid receptors (MORs), which mediate the most potent pain relief. Notably, neuropathic pain causes a reduction in MOR antinociceptive efficacy, which can be reversed by blocking spinal NMDARs and TRPA1 channels. Thus, we studied whether TRPA1 channels form complexes with MORs and NMDARs that may be implicated in the aforementioned nociceptive signals. Our data suggest that TRPA1 channels functionally associate with MORs, delta opioid receptors and NMDARs in the dorsal root ganglia, the spinal cord and brain areas. These associations were altered in response to pharmacological interventions and the induction of inflammatory and also neuropathic pain. The MOR-TRPA1 and NMDAR-TRPA1 associations do not require HINT1 or σ1R but appear to be mediated by calcium-activated calmodulin. Thus, TRPA1 channels may associate with NMDARs to promote ascending acute and chronic pain signals and to control MOR antinociception.MICINN Plan Nacional I+D+i RT 2018-093677B-100University of Granada PPJIB2019.11MECD FPU 15/02356 FPU16/0321

Optically-faint massive Balmer Break Galaxies at z>3 in the CANDELS/GOODS fields

We present a sample of 33 Balmer Break Galaxies (BBGs) selected as HST/F160W dropouts in the deepest CANDELS/GOODS fields ($H\gtrsim27.3$~mag) but relatively bright in {\it Spitzer}/IRAC ($[3.6],[4.5]<24.5$~mag), implying red colors (median and quartiles: $\langle H-[3.6]\rangle=3.1^{3.4}_{2.8}$\,mag). Half of these BBGs are newly identified sources. Our BBGs are massive ($\langle \log(\rm{M}/\rm{M}_\odot)\rangle=10.8$) high redshift ($\langle z\rangle=4.8$) dusty ($\langle \rm{A(V)}\rangle=2.0$~mag) galaxies. The SEDs of half of our sample indicate that they are star-forming galaxies with typical specific SFRs 0.5-1.0~Gyr$^{-1}$, qualifying them as main sequence (MS) galaxies at $3<z<6$. One third of those SEDs indicates the presence of prominent emission lines (H$\beta$+$[OIII]$, H$\alpha$$+$[NII]) boosting the IRAC fluxes and red colors. Approximately 20\% of the BBGs are very dusty ($\rm{A(V)}\sim2.5$~mag) starbursts with strong mid-to-far infrared detections and extreme SFRs ($\rm{SFR}>10^{3}\,\rm{M}_\odot/yr$) that place them above the MS. The rest, 30\%, are post-starbursts or quiescent galaxies located $>2\sigma$ below the MS with mass-weighted ages older than 700~Myr. Only 2 of the 33 galaxies are X-ray detected AGN with optical/near-infrared SEDs dominated by stellar emission, but the presence of obscured AGN in the rest of sources cannot be discarded. Our sample accounts for 8\% of the total number density of $\log(\rm{M}/\rm{M}_\odot)>10$ galaxies at $z>3$, but it is a significant contributor (30\%) to the general population of red $\log(\rm{M}/\rm{M}_\odot)>11$ galaxies at $4<z<6$. Finally, our results point out that 1 of every 30 massive $\log(\rm{M}/\rm{M}_\odot)>11$ galaxies in the local Universe was assembled in the first 1.5~Gyr after the Big Bang, a fraction that is not reproduced by state-of-the-art galaxy formation simulations.Comment: 38 pages, 18 figures, Accepted for publication in The Astrophysical Journal 26/03/201

Impact of a Community Intervention for Early Skin Cancer Diagnosis Implementing Teledermatology

The principal cause of skin cancer is sun exposure. In areas with high sun exposure levels, early diagnosis and sun protection education strategies must be developed. Aim of the study was to evaluate the impact of an early skin cancer diagnosis intervention implementing teledermatology. Transversal descriptive study on a population in the Western Costa del Sol. Primary care physicians were instructed on skin cancer diagnosis. They recruited consecutive at-risk patients and held four workshops for early skin cancer diagnosis and education on sun protection. The resulting variables on participants’ satisfaction and intention to change were collected. 393 patients were recruited. The mean age was 52.9 years, and 65.4% were women. Suspicious lesions were detected in 24.1% of participants, and 11.7% were attended to via teledermatology. Of these, 65.2% were evaluated in person at the Dermatology Department. Fourteen basal cell carcinomas, 5 squamous cell carcinomas, and 2 melanomas were diagnosed. Regarding patient satisfaction, 67.7% found all aspects of the workshops of interest, 41.7% found the skin check-up of interest, and 26.4% found sun and skin cancer prevention information of interest. Of the patients attended to via teledermatology, 100% stated it was good or very good and 100% would consult again via this method. The intervention was successful in terms of participation, skin cancer diagnosis, and satisfaction, especially compared with other international campaigns. Therefore, although the data cannot be extrapolated to all environments, this initiative may be used as the basis for the development of future interventions

Efficacy of prompted voiding for reversing urinary incontinence in older adults hospitalized in a functional recovery unit: Study protocol

Aims: To assess the efficacy of a prompted voiding programme for restoring urinary continence at discharge in hospitalized older adults who presented with reversible urinary incontinence (UI) on admission to a functional recovery unit (FRU). To assess the maintenance of the outcomes achieved after hospitalization. To identify modifiable and unmodifiable factors associated with the success of the prompted voiding programme. Design: Quasi-experimental, pre-/post-intervention study without a control group. Methods: Participants were aged 65 and over with a history of reversible UI in the previous year who had been admitted to a FRU and were on a prompted voiding programme throughout their hospitalization period. The sample consisted of 221 participants. A non-probabilistic sampling method, in order of recruitment after signing the informed consent form, was used. The primary outcomes were UI assessed at discharge and 1 month, 3 months and 6 months after discharge. Funding was granted in July 2019 by the Spain Health Research Fund (PI19/00168, Ministry of Health). The proposal was approved by the Spanish Research Ethics Committee. Discussion: The prompted voiding programme described can reverse UI or decrease the frequency and amount of urine loss in hospitalized older adults. Impact: Urinary incontinence is highly prevalent in hospitalized older adults. There is a need for care aimed at prevention, recovery and symptom control. Prompted voiding is a therapy provided by the nursing team during hospitalization and can also be provided by family caregivers at home after receiving proper training by the nursing team. Prompted voiding will enhance the health, functional ability and quality of life of older adults with UI, resulting in the reduction of associated healthcare costs and the risk of developing complicationsThis study has been funded by Instituto de Salud Carlos III through the project “PI19/00168” (Co-funded by European Regional Development Fund/ European Social Fund “A way to make Europe”/“Investing in your future”

The sigma-1 receptor curtails endogenous opioid analgesia during sensitization of TRPV1 nociceptors

Background and Purpose: Peripheral sensitization contributes to pathological pain. While prostaglandin E2 (PGE2) and nerve growth factor (NGF) sensitize peptidergic C-nociceptors (TRPV1+), glial cell line-derived neurotrophic factor (GDNF) sensitizes non-peptidergic C-neurons (IB4+). Sigma-1 receptor (σ1R) is a Ca2+-sensing chaperone known to modulate analgesia induced by opioid drugs. This receptor binds both to TRPV1 and the µ-opioid receptor (MOPr), although the functional repercussions of these physical interactions in peripheral sensitization are unknown. Experimental Approach: We tested the effect of sigma-1 antagonism on PGE2-, NGF- and GDNF-induced mechanical and heat hyperalgesia in mice. We used immunohistochemistry to determine the presence of endomorphin-2, an endogenous MOPr agonist, on dorsal root ganglion (DRG) neurons. Recombinant proteins were used to study the interactions between σ1R, MOPr and TRPV1. We used calcium imaging to study the effects of sigma-1 antagonism on PGE2-induced sensitization of TRPV1+ nociceptors. Key Results: σ1R antagonists reversed PGE2- and NGF-induced hyperalgesia, but not GDNF-induced hyperalgesia. Endomorphin-2 was detected on TRPV1+ but not on IB4+ neurons. Peripheral opioid receptor antagonism by naloxone methiodide or administration of an anti-endomorphin-2 antibody to a sensitized paw, reversed the antihyperalgesia induced by sigma-1 antagonists. Sigma-1 antagonism transfers σ1R from TRPV1 to MOPr, suggesting that σ1R participate in TRPV1-MOPr crosstalk. Moreover, σ1R antagonism reversed, in a naloxone-sensitive manner, PGE2-induced sensitization of DRG neurons to the calcium flux elicited by capsaicin, the prototypic TRPV1 agonist. Conclusion and Implications: σ1R antagonism harnesses endogenous opioids produced by TRPV1+ neurons to reduce hyperalgesia by increasing MOPr activity

Innovando en la Gestión académica: La incorporación de protocolos y herramientas digitales en los Grados de la Facultad de Ciencias Políticas y Sociología

Proyecto de Innovación en la Gestión Académica que tiene como objetivos principales incorporar protocolos y herramientas para la mejora en la Calidad de la gestión académica de los Grados. Principalmente aplicables a la coordinación docente de los Grados, la organización académica de los Trabajos Fin de Grado, la difusión e información de los estudios de Grado, el mantenimiento de la información web de los Grados, el reconocimiento de Créditos, y, la acogida, tutela y asesoramiento de los estudiantes de los Grados