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 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

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 phenotypeNeurofarmacología del dolor de la Universidad de Granada (CTS-109)FPU grants from the Spanish Ministry of Education, Culture and Sports.Spanish Ministry of Economy and Competitiveness (MINECO, grant SAF2016-80540-R)the Junta de Andalucía (grant CTS 109)Esteve PharmaceuticalsEuropean Regional Development Fund (ERDF

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

Sigma-1 receptor inhibition ameliorates neuropathic pain induced by nerve transection

El receptor sigma-1 es una proteína chaperona regulada por ligando que bajo situaciones de estrés celular migra desde el retículo endoplásmico a la membrana plasmática, modulando la actividad de varios canales iónicos y receptores acoplados a proteínas G con los que interacciona físicamente. El receptor sigma-1 es una diana muy prometedora para el tratamiento del dolor neuropático, dónde ha sido ampliamente estudiado a nivel preclínico (Sánchez-Fernández et al., 2017). Entre los antagonistas selectivos sigma-1, el que ha sido caracterizado en mayor profundidad es el S1RA (Vela et al., 2015). Este fármaco ha sido evaluado en ensayos clínicos de fase II en pacientes con dolor neuropático inducido por quimioterapia, con resultados prometedores (Bruna et al., 2018). Aunque ya ha sido descrito el papel de la inhibición del receptor sigma-1 en modelos preclínicos de dolor neuropático inducidos por ligadura o constricción de nervios periféricos (Romero et al., 2012; Espinosa-Juárez et al., 2017), se desconoce su papel en la neuropatía producida por la sección de un nervio periférico. Realizar este estudio es interesante pues durante las intervenciones quirúrgicas (como toracotomía o mastectomía) la sección de nervios resulta inevitable, y como consecuencia, un gran número de pacientes desarrollan dolor neuropático postquirúrgico (Borsook et al., 2013). Además, los patrones de las alteraciones sensoriales así como los cambios de expresión génicos y neuroplásticos difieren entre los modelos de ligadura/constricción de nervio y los de denervación (Casals-Diaz et al. 2009), lo que podría implicar que la respuesta farmacológica fuese diferente también. Por ello, en esta Tesis hemos evaluado el papel del receptor sigma-1 en la neuropatía que se produce en el modelo de lesión de nervio compartido (SNI, por sus siglas en inglés Spared Nerve Injury). El SNI consiste en seccionar dos de las tres ramas del nervio ciático dejando la rama sural intacta (Decosterd y Woolf, 2000). Por otra parte, se sabe que el receptor sigma-1 modula la analgesia opioide endógena periférica producida por ciertas células inmunitarias en el foco inflamatorio, contribuyendo a controlar el dolor (Tejada et al., 2018). Sin embargo, se desconoce por completo si los receptores sigma-1 también modulan esta analgesia opioide endógena durante el dolor neuropático.Tesis Univ. Granada.Junta de Andalucía (grupo CTS-109 y Proyecto Motriz de Excelencia P11-CTS-7649)Ministerio de Economía y Competitividad (proyecto SAF2016-80540-R)fondos FEDERLaboratorios Estev

Paclitaxel antitumor effect improvement in lung cancer and prevention of the painful neuropathy using large pegylated cationic liposomes

Paclitaxel (PTX), a drug widely used in lung cancer, has serious limitations including the development of peripheral neurotoxicity, which may lead to treatment discontinuation and therapy failure. The transport of PTX in large cationic liposomes could avoid this undesirable effect, improving the patient’s prognosis. PTX was encapsulated in cationic liposomes with two different sizes, MLV (180-200 nm) and SUV (80-100 nm). In both cases, excellent biocompatibility and improved internalization and antitumor effect of PTX were observed in human and mice lung cancer cells in culture, multicellular spheroids and cancer stem cells (CSCs). In addition, both MLV and SUV with a polyethylene glycol (PEG) shell, induced a greater tumor volume reduction than PTX (56.4 % and 57.1 % vs. 36.7 %, respectively) in mice. Interestingly, MLV-PEG-PTX did not induce either mechanical or heat hypersensitivity whereas SUV-PEG-PTX produced a similar response to free PTX. Analysis of PTX distribution showed a very low concentration of the drug in the dorsal root ganglia (DRG) with MLV-PEG-PTX, but not with SUV-PEG-PTX or free PTX. These results support the hypothesis that PTX induces peripheral neuropathy by penetrating the endothelial fenestrations of the DRG (80-100 nm, measured in mice). In conclusion, our larger liposomes (MLV-PEG-PTX) not only showed biocompatibility, antitumor activity against CSCs, and in vitro and in vivo antitumor effect that improved PTX free activity, but also protected from PTX-induced painful peripheral neuropathy. These advantages could be used as a new strategy of lung cancer chemotherapy to increase the PTX activity and reduce its side effects.Junta de Andalucía P11-CTS-7649 PI-0102-2017 P18-TP-3882 CTS-107CTS-107 GroupInstituto de Salud Carlos III PI19/0147

Mechanistic Differences in Neuropathic Pain Modalities Revealed by Correlating Behavior with Global Expression Profiling

SUMMARY Chronic neuropathic pain is a major morbidity of neural injury, yet its mechanisms are incompletely understood. Hypersensitivity to previously non-noxious stimuli (allodynia) is a common symptom. Here, we demonstrate that the onset of cold hypersensitivity precedes tactile allodynia in a model of partial nerve injury, and this temporal divergence was associated with major differences in global gene expression in innervating dorsal root ganglia. Transcripts whose expression change correlates with the onset of cold allodynia were nociceptor related, whereas those correlating with tactile hypersensitivity were immune cell centric. Ablation of TrpV1 lineage nociceptors resulted in mice that did not acquire cold allodynia but developed normal tactile hypersensitivity, whereas depletion of macrophages or T cells reduced neuropathic tactile allodynia but not cold hypersensitivity. We conclude that neuropathic pain incorporates reactive processes of sensory neurons and immune cells, each leading to distinct forms of hypersensitivity, potentially allowing drug development targeted to each pain type