Nociceptor-immune interactomes reveal insult-specific immune signatures of pain.

Inflammatory pain results from the heightened sensitivity and reduced threshold of nociceptor sensory neurons due to exposure to inflammatory mediators. However, the cellular and transcriptional diversity of immune cell and sensory neuron types makes it challenging to decipher the immune mechanisms underlying pain. Here we used single-cell transcriptomics to determine the immune gene signatures associated with pain development in three skin inflammatory pain models in mice: zymosan injection, skin incision and ultraviolet burn. We found that macrophage and neutrophil recruitment closely mirrored the kinetics of pain development and identified cell-type-specific transcriptional programs associated with pain and its resolution. Using a comprehensive list of potential interactions mediated by receptors, ligands, ion channels and metabolites to generate injury-specific neuroimmune interactomes, we also uncovered that thrombospondin-1 upregulated by immune cells upon injury inhibited nociceptor sensitization. This study lays the groundwork for identifying the neuroimmune axes that modulate pain in diverse disease contexts.

Sigma-1 receptors control neuropathic pain and macrophage infiltration into the dorsal root ganglion after peripheral nerve injury.

Neuron-immune interaction in the dorsal root ganglia (DRG) plays a pivotal role in the neuropathic pain development after nerve injury. Sigma-1 receptor (Sig-1R) is expressed by DRG neurons but its role in neuropathic pain is not fully understood. We investigated the effect of peripheral Sig-1R on neuroinflammation in the DRG after spared (sciatic) nerve injury (SNI) in mice. Nerve injury induced a decrease in NeuN staining along with the nuclear eccentricity and ATF3 expression in the injured DRG. Sig-1R was present in all DRG neurons examined, and after SNI this receptor translocated to the periphery of the soma and the vicinity of the nucleus, especially in injured ATF3 + neurons. In WT mice, injured DRG produced the chemokine CCL2, and this was followed by massive infiltration of macrophages/monocytes, which clustered mainly around sensory neurons with translocated Sig-1R, accompanied by robust IL-6 increase and mechanical allodynia. In contrast, Sig-1R knockout (Sig-1R-KO) mice showed reduced levels of CCL2, decreased macrophage/monocyte infiltration into DRG, and less IL-6 and neuropathic mechanical allodynia after SNI. Our findings point to an important role of peripheral Sig-1R in sensory neuron-macrophage/monocyte communication in the DRG after peripheral nerve injury; thus, these receptors may contribute to the neuropathic pain phenotype.

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. Several experimental models of pathological pain are considered, including peripheral and central neuropathic pain, osteoarthritic, and cancer pain. Sigma-1 receptor inhibition prevents peripheral (macrophage infiltration into the dorsal root ganglion) and central (activation of microglia and astrocytes) neuroinflammation in several pain models, and enhances immune-driven peripheral opioid analgesia during painful inflammation, maximizing the analgesic potential of peripheral immune cells. Therefore, sigma-1 antagonists may constitute a new class of analgesics with an unprecedented mechanism of action and potential utility in several painful disorders.

Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice.

Sigma-1 antagonism potentiates the antinociceptive effects of opioid drugs, so sigma-1 receptors constitute a biological brake to opioid drug-induced analgesia. The pathophysiological role of this process is unknown. We aimed to investigate whether sigma-1 antagonism reduces inflammatory pain through the disinhibition of the endogenous opioidergic system in mice. The selective sigma-1 antagonists BD-1063 and S1RA abolished mechanical and thermal hyperalgesia in mice with carrageenan-induced acute (3 h) inflammation. Sigma-1-mediated antihyperalgesia was reversed by the opioid antagonists naloxone and naloxone methiodide (a peripherally restricted naloxone analog) and by local administration at the inflamed site of monoclonal antibody 3-E7, which recognizes the pan-opioid sequence Tyr-Gly-Gly-Phe at the N terminus of most endogenous opioid peptides (EOPs). Neutrophils expressed pro-opiomelanocortin, the precursor of ß-endorphin (a known EOP), and constituted the majority of the acute immune infiltrate. ß-endorphin levels increased in the inflamed paw, and this increase and the antihyperalgesic effects of sigma-1 antagonism were abolished by reducing the neutrophil load with in vivo administration of an anti-Ly6G antibody. The opioid-dependent sigma-1 antihyperalgesic effects were preserved 5 d after carrageenan administration, where macrophages/monocytes were found to express pro-opiomelanocortin and to now constitute the majority of the immune infiltrate. These results suggest that immune cells harboring EOPs are needed for the antihyperalgesic effects of sigma-1 antagonism during inflammation. In conclusion, sigma-1 receptors curtail immune-driven peripheral opioid analgesia, and sigma-1 antagonism produces local opioid analgesia by enhancing the action of EOPs of immune origin, maximizing the analgesic potential of immune cells that naturally accumulate in painful inflamed areas.

Amelanotic melanoma in a patient with oculocutaneous albinism.

Oculocutaneous albinism is a genetically heterogeneous, autosomal recessive group of disorders characterized by a generalized decreased or absence of melanin pigment in the eyes, hair, and skin. These patients have a greater sensitivity to UV radiation and a predisposition to skin tumors, mainly squamous cell carcinoma and basal cell carcinomas, and to a lesser extent malignant melanomas. Melanoma can be one of the most challenging cancers to diagnose in patients with albinism. We report an uncommon clinical presentation of melanoma, an amelanotic melanoma in the right supraciliar region in a patient with oculocutaneous albinism. The clinical presentation was an erythematous, scaly and ill-defined plaque. The skin biopsy revealed a lentigo maligna melanoma. Amelanotic melanomas are one of the two most difficult to diagnose subtypes of melanoma, together with the nevoid type. Melanoma in oculocutaneous albinism patients are often amelanotic, which makes their clinical diagnosis very difficult. These patients should be examined in the dermatology department at least once a year and it is recommended to have a high index of suspicion.

Solitary circumscribed neuroma of the glans penis. An unusual finding.

Palisaded encapsulated neuroma is a rare, benign neural tumor. The involvement of the glans penis is rare; few cases have been reported. We present a 52-year-old man with a five-month course of a solitary painless lesion of the glans penis. Full excision of the nodule was performed. Histopathological and immunohistochemical analyses and examination was consistent with a palisaded encapsulated neuroma. We describe one of a few existing cases of this kind of tumor in the glans penis.

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 system.

The frontal assessment battery in clinical practice: a systematic review.

BACKGROUND: The frontal assessment battery (FAB) is a brief tool designed to evaluate executive function. Some studies have particularly focused on assessing its applicability addressing two issues: first, on detecting the brain regions responsible for the FAB performance, and second, on determining its capability for differential diagnosis. Our aim was to summarize and analyze critically the studies that assessed the neuroanatomical correspondence and the differential diagnostic value of the FAB in several study populations suffering from different pathologies. METHODS: We completed a literature search in MEDLINE (via PubMed) database by using the term "frontal assessment battery" and the combination of this term with "applicability" or "use" or "usefulness". The search was limited to articles in English or Spanish languages, published between 1 September 2000 and 30 September 2016, human studies, and journal articles. RESULTS: A total of 32 studies met inclusion criteria. Seventeen studies were aimed at identifying the brain regions or the neural substrates involved in executive functions measured by the FAB and 15 studies at verifying that the FAB was an appropriate tool for the differential diagnosis in neurological diseases. CONCLUSION: Our study showed that the FAB may be an adequate assessment tool for executive function and may provide useful information for differential diagnosis in several diseases. Given that the FAB takes short time and is easy to administer, its usage may be of great interest as part of a full neuropsychological assessment in clinical settings. Copyright © 2017 John Wiley & Sons, Ltd.

Esophageal multichannel intraluminal impedance and pH testing in the study of apparent life threatening episode incidents in infants.

INTRODUCTION: The conventional 24-hour pH monitoring is the gold standard for the diagnosis of gastro-esophageal reflux (GER), a possible cause of Apparent Life Threatening Episodes (ALTE). However, multichannel intraluminal impedance (MII) may provide advantages. OBJECTIVES: Comparison of the results of MII and pH monitoring in patients undergoing MII-pH monitoring in the 3-year study period because of having suffered from ALTE. MATERIAL AND METHODS: Prospective study of MII-pH monitoring performed in our unit to infants < 12 months of ageadmitted for ALTE for a 3-year period. RESULTS: Thirty nine patients studied. 2,692 pH monitoring episodes, with median of 24 (IQ: 15-44) episodes/patient, 1.30 (IQ: 0.80-2.60) reflux/hour, 1 (IQ: 0-4) reflux episode > 5 min per patient and clearance of 1.20 (IQ: 0.70-2.20) min/reflux. With pH monitoring analysis, 14 children (35.9 %) could have been diagnosed as GER (8 mild, 4 moderate and 2 severe) based on the classical criteria. MII identified a total of 8,895 events; only 3,219 among them were refluxes, with a median of 75 (IQ: 54-111) per patient, 1.30 (IQ: 1.3-2.6) episodes/hour). With MII-pH monitoring combination there were 21.60 (SD 15.21) acid reflux episodes, 67.33 weekly acid (SD 32.09) and 3.34 (SD 7.23) non-acid, being finally diagnosed 33 patients as GER. CONCLUSIONS: The association of pH monitoring and MII provides additional information that improves GER diagnostic performance without posing any additional risk to the infant patient. The non-acid/weekly acid refluxes, not detected by pH monitoring, account for a high percentage of episodes, this may have diagnostic and therapeutic significance, especially in infants. Further studies are needed to assess the normality of MMI in pediatric patients.

Evaluation of infection prevention and control programmes according to the European Centre for Disease Prevention and Control and the World Health Organization in Spain 2012-2022: indicators of core component 1.

BACKGROUND: Key and core components of effective infection prevention and control programmes (IPCPs) issued by the European Centre for Disease Prevention and Control (ECDC) and the World Health Organization (WHO) have been described. WHO core component 1 relates to the structure, organization and management of IPCPs. AIM: The objective of this study was to assess the status and the time trends of some indicators of core component 1 of IPCPs in acute hospitals in Spain throughout the period 2012-2022. METHODS: Hospital-level data from the Spanish point prevalence survey for years 2012-2022 were analysed. Core component 1 indicators were calculated and tested for association to healthcare-associated infections (HAIs). In addition, trends were also examined. RESULTS: Overall, 67.0% and 57.2% of Spanish hospitals reported having an annual infection prevention and control (IPC) plan and an annual IPC report that was approved by the hospital managing director, respectively. The global median number of full-time equivalent (FTE) IPC nurses per 250 beds for the period was 0.87 and the global median number of FTE IPC doctors was 0.70. The rates of blood cultures and stool tests for Clostridioides difficile were 39.9 and 6.1 per 1000 patient-days, respectively. No significant correlation was found between core component 1 indicators and HAI prevalence. CONCLUSION: Spain is currently at a basic level on the structure, organization and management of IPCPs. Profound differences were found between hospitals depending on size and type.

Translation, Cross-Cultural Adaptation, and Feasibility of the NHPT-E of Manual Dexterity for the Spanish Population.

The Nine-Hole Peg Test (NHPT) is considered a "gold standard" for the measurement of manual dexterity. The aim of this study was the translation and culturally adapting the original version of the NHPT. MATERIALS AND METHODS: The adaptation was carried out following the standardized translation-retrotranslation guidelines and procedures referred to in the literature and in the International Test Commission (CIT). The final Spanish version of the NHPT (NHPT-E) was administered to 40 healthy adults. We evaluated its feasibility by means of a questionnaire elaborated according to Iraossi's checklist proposal for the pilot test process. RESULTS: Modifications of expression in the grammatical mode of the verbs were performed, as well as the adaptation of some terms used in the three sections of the original version of the test (General Information, Installation, and Application Instructions). In the pilot study, for 95% of the participants, the NHPT-E is a comfortable test to take, and, for 100% of the evaluators, the test includes all the necessary information, with clear instructions and interpretation of the results. CONCLUSIONS: The cross-cultural adaptation and pilot study enabled the development of a suitable and viable version of the NHPT-E for use in the Spanish population.

APPS-S: A Tool for Measuring the Attitudes Toward Prostitution and Women in Prostitution in the Spanish Population.

This study was designed with the purpose of testing the psychometric properties of the Spanish version of the Attitudes toward Prostitution and Prostitutes Scale through three studies with different samples. The first one explores the test's dimensional structure or constructs validity through confirmatory factor analysis, as well as internal consistency and test-retest reliability. The second one focuses on discriminant and criteria validity. Finally, the third one examines the scale's convergent validity and its sensitivity to detecting changes. The results support two subscales with an optimal index of internal consistency, structural stability over time, and discriminative power between groups of participants. It is, therefore, an adequate tool for adults as well as young people and teenagers, and for detecting changes in the context of intervention or awareness workshops.

Trends of antimicrobial use through selected antimicrobial indicators in Spanish hospitals, 2012 to 2021.

BACKGROUND: Surveillance of antimicrobial consumption is an important component of control strategies to tackle antimicrobial resistance. AIM: To evaluate the consumption of antimicrobials using six indicators proposed by the European Center for Disease Prevention and Control. METHODS: Point prevalence survey data on antimicrobial use in Spanish hospitals throughout the period 2012-2021 were analysed. A descriptive analysis of each indicator by year was performed globally and by hospital size. A logistic regression model was used to identify significant time trends. FINDINGS: In all, 515,414 patients and 318,125 antimicrobials were included. The prevalence of antimicrobial use remained stable throughout the study period (45.7%; 95% confidence interval (CI): 45.6-45.8). Percentages of antimicrobials for systemic use and those administered parenterally showed a small and significant increasing trend (odds ratio (OR): 1.02; 95% CI: 1.01-1.02; and OR: 1.03; 95% CI: 1.02-1.03, respectively). Small improvements were found in the percentages of antimicrobials prescribed for medical prophylaxis and with the reason for use documented in patients' medical records (-0.6% and 4.2%, respectively). The percentage of surgical prophylaxis prescribed for more than 24 h shows a significant improvement, decreasing from 49.9% (95% CI: 48.6-51.3) in 2012 to 37.1% (95% CI: 35.7-38.5) in 2021. CONCLUSION: During the last decade, Spanish hospitals have had a stable but high prevalence of antimicrobial use. Little to no improvement has been made in most of the indicators analysed, except for a reduction in the prescription of surgical prophylaxis for more than 24 h.

Perceptions of poverty in Spain: differences in the attitudinal profiles between women and men.

Poverty is a multidimensional phenomenon that encompasses privation of education, health or housing. Women show more positive perceptions of poor people, making external attributions for the causes of poverty or the circumstances that explain it. The aim of this study is to analyse perceptions of poverty, identifying the differences in attitudinal profiles between women and men, and the influence of their political and religious beliefs. The sample consists of 278 participants (154 women and 124 men), who completed a sociodemographic questionnaire and the Scale of Attitudes and Stereotypes toward Poverty. The results showed two attitude profiles for women and men, with differences in the first profile, where women or men did not have religious beliefs, had left-wing or centre-left political ideas and favourable attitudes about poverty.

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+). The sigma-1 receptor (sigma-1R) is a Ca2+ -sensing chaperone known to modulate opoid analgesia. This receptor binds both to TRPV1 and the µ opioid receptor, although the functional repercussions of these physical interactions in peripheral sensitization are unknown. EXPERIMENTAL APPROACH: We tested the effects 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 µ receptor agonist, on dorsal root ganglion (DRG) neurons. Recombinant proteins were used to study the interactions between sigma-1R, µ- receptor, and TRPV1. We used calcium imaging to study the effects of sigma-1 antagonism on PGE2-induced sensitization of TRPV1+ nociceptors. KEY RESULTS: Sigma1 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 sigma-1R from TRPV1 to µ receptors, suggesting that sigma-1R participate in TRPV1-µ receptor crosstalk. Moreover, sigma-1 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: Sigma-1 antagonism harnesses endogenous opioids produced by TRPV1+ neurons to reduce hyperalgesia by increasing µ receptor activity.

Sigma-1 receptor agonism exacerbates immune-driven nociception: Role of TRPV1 + nociceptors.

The analgesic effects of sigma-1 antagonists are undisputed, but the effects of sigma-1 agonists on pain are not well studied. Here, we used a mouse model to show that the administration of the sigma-1 agonists dextromethorphan (a widely used antitussive drug), PRE-084 (a standard sigma-1 ligand), and pridopidine (a selective drug being investigated in clinical trials for the treatment of neurodegenerative diseases) enhances PGE2-induced mechanical hyperalgesia. Superficial plantar incision induced transient weight-bearing asymmetry at early time points, but the mice appeared to recover at 24 h, despite noticeable edema and infiltration of neutrophils (a well-known cellular source of PGE2) at the injured site. Sigma-1 agonists induced a relapse of weight bearing asymmetry in a manner dependent on the presence of neutrophils. The effects of sigma-1 agonists were all reversed by administration of the sigma-1 antagonist BD-1063 in wild-type mice, and were absent in sigma-1 knockout mice, supporting the selectivity of the effects observed. The proalgesic effects of sigma-1 agonism were also abolished by the TRP antagonist ruthenium red and by in vivo resiniferatoxin ablation of TRPV1 + peripheral sensory neurons. Therefore, sigma-1 agonism exacerbates pain-like responses in mice with a mild inflammatory state through the action of TRPV1 + nociceptors. We also show that sigma-1 receptors are present in most (if not all) mouse and human DRG neurons. If our findings translate to humans, further studies will be needed to investigate potential proalgesic effects induced by sigma-1 agonism in patients treated with sigma-1 agonists.

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. The most promising compounds were subjected to in vitro toxicity testing and subsequently screened for in vivo analgesic properties. Compound 9d (AD258) exhibited negligible in vitro cellular toxicity and a high binding affinity to both SRs (KiS1R = 3.5 nM, KiS2R = 2.6 nM), but not for other pain-related targets, and exerted high potency in a model of capsaicin-induced allodynia, reaching the maximum antiallodynic effect at very low doses (0.6-1.25 mg/kg). Functional activity experiments showed that S1R antagonism is needed for the effects of 9d and that it did not induce motor impairment. In addition, 9d exhibited a favorable pharmacokinetic profile.

Dual Piperidine-Based Histamine H3 and Sigma-1 Receptor Ligands in the Treatment of Nociceptive and Neuropathic Pain.

In search of new dual-acting histamine H3/sigma-1 receptor ligands, we designed a series of compounds structurally based on highly active in vivo ligands previously studied and described by our team. However, we kept in mind that within the previous series, a pair of closely related compounds, KSK67 and KSK68, differing only in the piperazine/piperidine moiety in the structural core showed a significantly different affinity at sigma-1 receptors (σ1Rs). Therefore, we first focused on an in-depth analysis of the protonation states of piperazine and piperidine derivatives in the studied compounds. In a series of 16 new ligands, mainly based on the piperidine core, we selected three lead structures (3, 7, and 12) for further biological evaluation. Compound 12 showed a broad spectrum of analgesic activity in both nociceptive and neuropathic pain models based on the novel molecular mechanism.

Bibliometric Analysis of Research on the Use of the Nine Hole Peg Test.

Manual dexterity is essential for performing daily life tasks, becoming a primary means of interaction with the physical, social, and cultural environment. In this respect, the Nine Hole Peg Test (NHPT) is considered a gold standard for assessing manual dexterity. Bibliometrics is a discipline that focuses on analyzing publications to describe, evaluate, and predict the status and development trends in certain fields of scientific research. We performed a bibliometric analysis to track research results and identify global trends regarding the use of the NHPT. The bibliographic data were retrieved from the Web of Science database and then analyzed using the Bibliometrix R package, resulting in the retrieval of a total of 615 publications from 1988 to 2021. Among the 263 journals investigated, the most prolific were the Multiple Sclerosis Journal, Clinical Rehabilitation, and Multiple Sclerosis and Related Disorders. North America and Europe were the areas with the highest production of publications, with the United States (n = 104) ranking first in terms of the number of publications, followed by the United Kingdom (n = 62) and Italy (n = 62). The analysis of keywords revealed that there were two main lines of research, with one related to the study of recovery and disability of the upper limbs caused by certain diseases and another related to the study of reliability and validity. Structured information can be useful to understand the research trajectory and the uses of this tool.