Pharmacological differences in postoperative cutaneous sensitivity, pain at rest, and movement-induced pain in laparotomized mice.

Postoperative pain management is challenging. We used mice with a transverse laparotomy to study tactile allodynia measured by the von Frey test, pain at rest measured by facial pain expressions detected by an artificial intelligence algorithm, and movement-induced pain measured by reductions in exploratory activity. The standard analgesics morphine and ibuprofen induced distinct patterns of outcome-dependent effects.

Sigma-1 Receptors Control Neuropathic Pain and Peripheral Neuroinflammation After Nerve Injury in Female Mice: A Transcriptomic Study.

The mechanisms for neuropathic pain amelioration by sigma-1 receptor inhibition are not fully understood. We studied genome-wide transcriptomic changes (RNAseq) in the dorsal root ganglia (DRG) from wild-type and sigma-1 receptor knockout mice prior to and following Spared Nerve Injury (SNI). In wildtype mice, most of the transcriptomic changes following SNI are related to the immune function or neurotransmission.

Exploring the Effects of Robertsonian Translocation 1/29 (Rob (1;29)) on Genetic Diversity in Minor Breeds of Spanish Berrenda Cattle via Genome-Wide Analysis.

Most of the previous studies on the genetic variability in Spanish "Berrenda" breeds have been carried out using DNA microsatellites. The present work aimed to estimate the genetic diversity, population structure, and potential genetic differences among individuals of both Berrenda breeds and groups based on the presence of the Robertsonian chromosomal translocation, rob (1;29). A total of 373 samples from animals belonging to the two breeds, including 169 cases diagnosed as rob (1;29)-positive, were genotyped using an SNP50K chip.

Quantification of stimulus-evoked tactile allodynia in free moving mice by the chainmail sensitivity test.

Chronic pain occurs at epidemic levels throughout the population. Hypersensitivity to touch, is a cardinal symptom of chronic pain. Despite dedicated research for over a century, quantifying this hypersensitivity has remained impossible at scale.

Discovery of AD258 as a Sigma Receptor Ligand with Potent Antiallodynic Activity.

The design and synthesis of a series of 2,7-diazaspiro[4.4]nonane derivatives as potent sigma receptor (SR) ligands, associated with analgesic activity, are the focus of this work. In this study, affinities at S1R and S2R were measured, and molecular modeling studies were performed to investigate the binding pose characteristics.

Synthesis, Computational Insights, and Evaluation of Novel Sigma Receptors Ligands.

The development of diazabicyclo[4.3.0]nonane and 2,7-diazaspiro[3.

Conformationally Restricted σ Receptor Antagonists from (-)-Isopulegol.

Antagonists at σ receptors have great potential for the treatment of neuropathic pain. Starting from monoterpene (-)-isopulegol (), aminodiols were obtained and transformed into bicyclic and tricyclic ligands . Aminodiols showed higher σ affinity than the corresponding bicyclic and tricyclic derivatives .

Synthesis, In Vitro Profiling, and In Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors.

The soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia.

Minocycline Prevents the Development of Key Features of Inflammation and Pain in DSS-induced Colitis in Mice.

Abdominal pain is a common feature in inflammatory bowel disease (IBD) patients, and greatly compromises their quality of life. Therefore, the identification of new therapeutic tools to reduce visceral pain is one of the main goals for IBD therapy. Minocycline, a broad-spectrum tetracycline antibiotic, has gained attention in the scientific community because of its immunomodulatory and anti-inflammatory properties.

Automated preclinical detection of mechanical pain hypersensitivity and analgesia.

The lack of sensitive and robust behavioral assessments of pain in preclinical models has been a major limitation for both pain research and the development of novel analgesics. Here, we demonstrate a novel data acquisition and analysis platform that provides automated, quantitative, and objective measures of naturalistic rodent behavior in an observer-independent and unbiased fashion. The technology records freely behaving mice, in the dark, over extended periods for continuous acquisition of 2 parallel video data streams: (1) near-infrared frustrated total internal reflection for detecting the degree, force, and timing of surface contact and (2) simultaneous ongoing video graphing of whole-body pose.

Structural analysis of mixed α- and β-amyrin samples.

Little is known about the structure and molecular arrangement of α- and β-amyrin, a class of triterpenoids found within the cuticle of higher plants. Blends of both amyrin isomers with different ratios have been studied taking into consideration a combined methodology of density functional theory (DFT) calculations with experimental data from scanning electron microscopy, differential scanning calorimetry and Raman vibrational spectroscopy. Results indicate that trigonal trimeric aggregations of isomer mixtures are more stable, especially in the 1 : 2 ( : ) ratio.

GHG Emissions from Dairy Small Ruminants in Castilla-La Mancha (Spain), Using the ManleCO Simulation Model.

The first goal of this work was the description of a model addressed to quantify the carbon footprint in Spanish autochthonous dairy sheep farms (Manchega group), foreign dairy sheep farms (foreigners group: Lacaune and Assaf breeds), and Spanish autochthonous dairy goat farms (Florida group). The second objective was to analyze the GHG emission mitigation potential of 17 different livestock farming practices that were implemented by 36 different livestock farms, in terms of COe per hectare (ha), COe per livestock unit (LU), and COe per liter of fat- and protein-corrected milk (FPCM). The study showed the following results: 1.

Analyses of Genetic Diversity in the Endangered "Berrenda" Spanish Cattle Breeds Using Pedigree Data.

Pedigree analyses of two endangered cattle breeds were performed in order to study the structure and the genetic variability in their populations. Pedigree data were analyzed from 12,057 individuals belonging to the "Berrenda en Negro" cattle breed (BN) and 20,389 individuals belonging to the "Berrenda en Colorado" cattle breed (BC) that were born between 1983 and 2020. BN and BC reference populations (RP) were set up by 2300 and 3988 animals, respectively.

Synthesis of tropane-based σ receptor antagonists with antiallodynic activity.

Following the concept of conformational restriction to obtain high affinity σ ligands, the piperidine ring of eliprodil was replaced by the bicyclic tropane system and an exocyclic double bond was introduced. The envisaged benzylidenetropanes 9 were prepared by conversion of tropanone 10 into the racemic mixture of (Z)-14 and (E)-14. Reaction of racemate (Z)-14/(E)-14 with enantiomerically pure (R)- or (S)-configured 2-phenyloxirane provided mixtures of diastereomeric β-aminoalcohols (R,Z)-9 and (R,E)-9 as well as (S,Z)-9 and (S,E)-9, which were separated by chiral HPLC, respectively.

Dual Sigma-1 receptor antagonists and hydrogen sulfide-releasing compounds for pain treatment: Design, synthesis, and pharmacological evaluation.

The development of σ receptor antagonists hybridized with a HS-donor is here reported. We aimed to obtain improved analgesic effects when compared to σ receptor antagonists or HS-donors alone. In an in vivo model of sensory hypersensitivity, thioamide 1a induced analgesia which was synergistically enhanced when associated with the σ receptor antagonist BD-1063.

Tetrodotoxin, a Potential Drug for Neuropathic and Cancer Pain Relief?

Tetrodotoxin (TTX) is a potent neurotoxin found mainly in puffer fish and other marine and terrestrial animals. TTX blocks voltage-gated sodium channels (VGSCs) which are typically classified as TTX-sensitive or TTX-resistant channels. VGSCs play a key role in pain signaling and some TTX-sensitive VGSCs are highly expressed by adult primary sensory neurons.

Structure determination of oleanolic and ursolic acids: a combined density functional theory/vibrational spectroscopy methodology.

Raw samples of oleanolic and ursolic acids, a class of terpenoid acids mainly found in the leaf and fruit cuticles of some plant species, can be defined as a blend of clusters of different conformers aggregated in dimers and tetramers by means of hydrogen bonds and stabilized by non-electrostatic interactions.

Intracolonic Mustard Oil Induces Visceral Pain in Mice by TRPA1-Dependent and -Independent Mechanisms: Role of Tissue Injury and P2X Receptors.

Both TRPA1 and purinergic P2X receptors have been proposed as potential targets for the treatment of visceral pain. We found that the intracolonic administration of a low dose mustard oil (0.5%), a well-known TRPA1 agonist, produced nociceptive responses and abdominal wall referred mechanical hyperalgesia, without inducing apparent tissue damage.

Two independent mouse lines carrying the Nav1.7 I228M gain-of-function variant display dorsal root ganglion neuron hyperexcitability but a minimal pain phenotype.

Small-fiber neuropathy (SFN), characterized by distal unmyelinated or thinly myelinated fiber loss, produces a combination of sensory dysfunction and neuropathic pain. Gain-of-function variants in the sodium channel Nav1.7 that produce dorsal root ganglion (DRG) neuron hyperexcitability are present in 5% to 10% of patients with idiopathic painful SFN.

Sigma-1 receptor: A drug target for the modulation of neuroimmune and neuroglial interactions during chronic pain.

Immune and glial cells play a pivotal role in chronic pain. Therefore, it is possible that the pharmacological modulation of neurotransmission from an exclusively neuronal perspective may not be enough for adequate pain management, and the modulation of complex interactions between neurons and other cell types might be needed for successful pain relief. In this article, we review the current scientific evidence for the modulatory effects of sigma-1 receptors on communication between the immune and nervous systems during inflammation, as well as the influence of this receptor on peripheral and central neuroinflammation.

Microwave-assisted functionalization of carbon nanohorns with oligothiophene units with SERS activity.

Carbon nanohorns have been functionalized with oligothiophene units via the 1,3-dipolar cycloaddition reaction under microwave irradiation and solvent-free conditions. A dramatic Raman enhancement was found for one of the synthesized derivatives. Experimental and in silico studies helped to understand the enhancement, attributed to the modification of electromagnetic fields upon functionalization at the tip of the nanostructures.

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.

Nonsurgical mouse model of endometriosis-associated pain that responds to clinically active drugs.

Endometriosis is an estrogen-dependent inflammatory disease that affects approximately 10% of women. Debilitating pelvic or abdominal pain is one of its major clinical features. Current animal models of endometriosis-associated pain require surgery either to implant tissue or to remove the ovaries.

Urinary bladder sigma-1 receptors: A new target for cystitis treatment.

No adequate treatment is available for painful urinary bladder disorders such as interstitial cystitis/bladder pain syndrome, and the identification of new urological therapeutic targets is an unmet need. The sigma-1 receptor (σ-R) modulates somatic pain, but its role in painful urological disorders is unexplored. The urothelium expresses many receptors typical of primary sensory neurons (e.