Grip strength in mice with joint inflammation: A rheumatology function test sensitive to pain and analgesia

Grip strength deficit is a measure of pain-induced functional disability in rheumatic disease. We tested whether this parameter and tactile allodynia, the standard pain measure in preclinical studies, show parallels in their response to analgesics and basic mechanisms. Mice with periarticular injections of complete Freund's adjuvant (CFA) in the ankles showed periarticular immune infiltration and synovial membrane alterations, together with pronounced grip strength deficits and tactile allodynia measured with von Frey hairs. However, inflammation-induced tactile allodynia lasted longer than grip strength alterations, and therefore did not drive the functional deficits. Oral administration of the opioid drugs oxycodone (1–8 mg/kg) and tramadol (10–80 mg/kg) induced a better recovery of grip strength than acetaminophen (40–320 mg/kg) or the nonsteroidal antiinflammatory drugs ibuprofen (10–80 mg/kg) or celecoxib (40–160 mg/kg); these results are consistent with their analgesic efficacy in humans. Functional impairment was generally a more sensitive indicator of drug-induced analgesia than tactile allodynia, as drug doses that attenuated grip strength deficits showed little or no effect on von Frey thresholds. Finally, ruthenium red (a nonselective TRP antagonist) or the in vivo ablation of TRPV1-expressing neurons with resiniferatoxin abolished tactile allodynia without altering grip strength deficits, indicating that the neurobiology of tactile allodynia and grip strength deficits differ. In conclusion, grip strength deficits are due to a distinct type of pain that reflects an important aspect of the human pain experience, and therefore merits further exploration in preclinical studies to improve the translation of new analgesics from bench to bedside.This study was partially supported by the Spanish Ministry of Economy and Competitiveness (MINECO, grant SAF2013-47481P), the Junta de Andalucía (grant CTS 109), and funding from Esteve and the European Regional Development Fund (FEDER)

Modulation by Sigma-1 Receptor of Morphine Analgesia and Tolerance: Nociceptive Pain, Tactile Allodynia and Grip Strength Deficits During Joint Inflammation

Sigma-1 receptor antagonism increases the effects of morphine on nociceptive pain, even in morphine-tolerant animals. However, it is unknown whether these receptors are able to modulate morphine antinociception and tolerance during inflammatory pain. Here we used a mouse model to test the modulation of morphine effects by the selective sigma-1 antagonist S1RA (MR309), by determining its effect on inflammatory tactile allodynia (von Frey filaments) and on grip strength deficits induced by joint inflammation (a measure of pain-induced functional disability), and compared the results with those for nociceptive heat pain recorded with the unilateral hot plate (55 C) test. The subcutaneous (s.c.) administration of morphine induced antinociceptive effects to heat stimuli, and restored mechanical threshold and grip strength in mice with periarticular inflammation induced by Complete Freund’s Adjuvant. S1RA (80 mg/kg, s.c.) administered alone did not induce any effect on nociceptive heat pain or inflammatory allodynia, but was able to partially reverse grip strength deficits. The association of S1RA with morphine, at doses inducing little or no analgesic-like effects when administered alone, resulted in a marked antinociceptive effect to heat stimuli and complete reversion of inflammatory tactile allodynia. However, S1RA administration did not increase the effect of morphine on grip strength deficits induced by joint inflammation.MT was supported by a postdoctoral grant from the University of Granada.MR-C and IB-C were supported by FPU grants from the Spanish Ministry of Economy and Competitiveness (MINECO). This study was partially supported by the Spanish Ministry of Economy and Competitiveness (Grants SAF2013-47481P and SAF2016-80540-R), the Junta de Andalucía (Grant CTS109), and FEDER funds

TARGETING IMMUNE-DRIVEN OPIOID ANALGESIA BY SIGMA-1 RECEPTORS: OPENING THE DOOR TO NOVEL PERSPECTIVES FOR THE ANALGESIC USE OF SIGMA-1 ANTAGONISTS

Immune cells have a known role in pronociception, since they release a myriad of inflammatory algogens which interact with neurons to facilitate pain signaling. However, these cells also produce endogenous opioid peptides with analgesic potential. The sigma-1 receptor is a ligand-operated chaperone that modulates neurotransmission by interacting with multiple protein partners, including the µ-opioid receptor. We recently found that sigma-1 antagonists are able to induce opioid analgesia by enhancing the action of endogenous opioid peptides of immune origin during inflammation. This opioid analgesia is seen only at the inflamed site, where immune cells naturally accumulate. In this article we review the difficulties of targeting the opioid system for selective pain relief, and discuss the dual role of immune cells in pain and analgesia. Our discussion creates perspectives for possible novel therapeutic uses of sigma-1 antagonists as agents able to maximize the analgesic potential of the immune systemUniversity of GranadaMartín Escudero postdoctoral programFPU grants from the Spanish Ministry of Economy and Competitiveness (MINECO)Juan de la Cierva-Incorporación postdoctoral grant from MINECOMINECO [grant number SAF2016-80540-R]Junta de Andalucía (grant CTS109)FEDER fund

The clinical heterogeneity of coenzyme Q10 deficiency results from genotypic differences in the Coq9 gene

Primary coenzyme Q10 (CoQ10) deficiency is due to mutations in genes involved in CoQ biosynthesis. The disease has been associated with five major phenotypes, but a genotype–phenotype correlation is unclear. Here, we compare two mouse models with a genetic modification in Coq9 gene (Coq9Q95X and Coq9R239X), and their responses to 2,4‐dihydroxybenzoic acid (2,4‐diHB). Coq9R239X mice manifest severe widespread CoQ deficiency associated with fatal encephalomyopathy and respond to 2,4‐diHB increasing CoQ levels. In contrast, Coq9Q95X mice exhibit mild CoQ deficiency manifesting with reduction in CI+III activity and mitochondrial respiration in skeletal muscle, and late‐onset mild mitochondrial myopathy, which does not respond to 2,4‐diHB. We show that these differences are due to the levels of COQ biosynthetic proteins, suggesting that the presence of a truncated version of COQ9 protein in Coq9R239X mice destabilizes the CoQ multiprotein complex. Our study points out the importance of the multiprotein complex for CoQ biosynthesis in mammals, which may provide new insights to understand the genotype–phenotype heterogeneity associated with human CoQ deficiency and may have a potential impact on the treatment of this mitochondrial disorder.This work was supported by grants from the Marie Curie International Reintegration Grant Programme (COQMITMEL-266691 to LCL) within the Seventh European Community Framework Programme, from Ministerio de Economía y Competitividad, Spain (SAF2009-08315 and SAF2013-47761-R to LCL), from the Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía (P10-CTS-6133 to LCL), and from the ‘CEIBioTic’ (20F12/1 to LCL). MLS is a predoctral fellow from the Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía. LCL is supported by the ‘Ramón y Cajal’ National Programme, Ministerio de Economía y Competitividad, Spain (RYC-2011-07643). MAT is supported by a predoctoral grant from the University of Granada. EJC is supported by the Research Program of the University of Granada. CMQ is supported by NICHD Grants 5K23 HDO65871-05 and P01 HD080642-01, and by a MDA grant. The proteomic analysis was performed in the CSIC/UAB Proteomics Facility of IIBB-CSIC that belongs to ProteoRed, PRB2-ISCIII, supported by Grant PT13/0001

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

Materialidad pictórica. Estudio y percepción de la pintura tardogótica en la actualidad

Estudio con carácter científico e interdisciplinar de los estudios físicos, químicos y visuales de los aspectos materiales e históricos de las pinturas tardogóticas en Castilla, y su difusión a través de las redes sociales de forma visual y didáctica

Comprehensive description of clinical characteristics of a large systemic Lupus Erythematosus Cohort from the Spanish Rheumatology Society Lupus Registry (RELESSER) with emphasis on complete versus incomplete lupus differences

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ involvement and pronounced racial and ethnic heterogeneity. The aims of the present work were (1) to describe the cumulative clinical characteristics of those patients included in the Spanish Rheumatology Society SLE Registry (RELESSER), focusing on the differences between patients who fulfilled the 1997 ACR-SLE criteria versus those with less than 4 criteria (hereafter designated as incomplete SLE (iSLE)) and (2) to compare SLE patient characteristics with those documented in other multicentric SLE registries. RELESSER is a multicenter hospital-based registry, with a collection of data from a large, representative sample of adult patients with SLE (1997 ACR criteria) seen at Spanish rheumatology departments. The registry includes demographic data, comprehensive descriptions of clinical manifestations, as well as information about disease activity and severity, cumulative damage, comorbidities, treatments and mortality, using variables with highly standardized definitions. A total of 4.024 SLE patients (91% with ≥4 ACR criteria) were included. Ninety percent were women with a mean age at diagnosis of 35.4 years and a median duration of disease of 11.0 years. As expected, most SLE manifestations were more frequent in SLE patients than in iSLE ones and every one of the ACR criteria was also associated with SLE condition; this was particularly true of malar rash, oral ulcers and renal disorder. The analysis-adjusted by gender, age at diagnosis, and disease duration-revealed that higher disease activity, damage and SLE severity index are associated with SLE [OR: 1.14; 95% CI: 1.08-1.20 (P < 0.001); 1.29; 95% CI: 1.15-1.44 (P < 0.001); and 2.10; 95% CI: 1.83-2.42 (P < 0.001), respectively]. These results support the hypothesis that iSLE behaves as a relative stable and mild disease. SLE patients from the RELESSER register do not appear to differ substantially from other Caucasian populations and although activity [median SELENA-SLEDA: 2 (IQ: 0-4)], damage [median SLICC/ACR/DI: 1 (IQ: 0-2)], and severity [median KATZ index: 2 (IQ: 1-3)] scores were low, 1 of every 4 deaths was due to SLE activity. RELESSER represents the largest European SLE registry established to date, providing comprehensive, reliable and updated information on SLE in the southern European population

The search for translational pain outcomes to refine analgesic development: Where did we come from and where are we going?

Pain measures traditionally used in rodents record mere reflexes evoked by sensory stimuli; the results thus may not fully reflect the human pain phenotype. Alterations in physical and emotional functioning, pain-depressed behaviors and facial pain expressions were recently proposed as additional pain outcomes to provide a more accurate measure of clinical pain in rodents, and hence to potentially enhance analgesic drug development. We aimed to review how preclinical pain assessment has evolved since the development of the tail flick test in 1941, with a particular focus on a critical analysis of some nonstandard pain outcomes, and a consideration of how sex differences may affect the performance of these pain surrogates. We tracked original research articles in Medline for the following periods: 1973-1977, 1983-1987, 1993-1997, 2003-2007, and 2014-2018. We identified 606 research articles about alternative surrogate pain measures, 473 of which were published between 2014 and 2018. This indicates that preclinical pain assessment is moving toward the use of these measures, which may soon become standard procedures in preclinical pain laboratories.FPU grant from the Spanish Ministry of Education, Culture and SportsSpanish Ministry of Economy and Competitiveness (MINECO, grant SAF2016-80540-R)Ramón Areces FoundationJunta de Andalucía (grant CTS 109)Esteve PharmaceuticalsEuropean Regional Development Fund (ERDF

Control of opioid analgesis and tolerance by sigma-1 receptors: studies on nocipetivie and inflammatory joint pain

Tesis Univ. Granada.Programa Oficial de Doctorado en BiomedicinaLa realización de esta tesis ha sido posible gracias a la financiación de nuestro grupo de investigación por la Junta de Andalucía (grupo CTS-109), por el CEI BioTic Granada, por fondos FEDER, Ministerio de Ciencia e Innovación (proyectos SAF2013-47481P y SAF2016-80540-R), y Laboratorios Esteve

Control of opioid analgesis and tolerance by sigma-1 receptors: studies on nocipetivie and inflammatory joint pain

Tesis Univ. Granada.Programa Oficial de Doctorado en BiomedicinaLa realización de esta tesis ha sido posible gracias a la financiación de nuestro grupo de investigación por la Junta de Andalucía (grupo CTS-109), por el CEI BioTic Granada, por fondos FEDER, Ministerio de Ciencia e Innovación (proyectos SAF2013-47481P y SAF2016-80540-R), y Laboratorios Esteve