Grupo: Neurofarmacología del Dolor (CTS109)https://hdl.handle.net/10481/670062024-03-29T13:59:51Z2024-03-29T13:59:51ZDual sigma-1 receptor antagonists and hydrogen sulfide-releasing compounds for pain treatment: design, synthesis and pharmacological evaluationDichiara, MariaArtacho Cordón, AntoniaTurnaturi, RitaSantos Caballero, MiriamGonzález Cano, RafaelPasquinucci, LorellaBarbaraci, CarlaRodríguez Gómez, Isabel MaríaGómez Guzmán, ManuelMarrazzo, AgostinoCobos del Moral, Enrique JoséAmata, Emanuelehttps://hdl.handle.net/10481/754772022-06-14T09:15:47ZDual sigma-1 receptor antagonists and hydrogen sulfide-releasing compounds for pain treatment: design, synthesis and pharmacological evaluation
Dichiara, Maria; Artacho Cordón, Antonia; Turnaturi, Rita; Santos Caballero, Miriam; González Cano, Rafael; Pasquinucci, Lorella; Barbaraci, Carla; Rodríguez Gómez, Isabel María; Gómez Guzmán, Manuel; Marrazzo, Agostino; Cobos del Moral, Enrique José; Amata, Emanuele
The development of σ1 receptor antagonists hybridized with a H2S-donor is here reported. We aimed to obtain improved analgesic effects when compared to σ1 receptor antagonists or H2S-donors alone. In an in vivo model of sensory hypersensitivity, thioamide 1a induced analgesia which was synergistically enhanced when associated with the σ1 receptor antagonist BD-1063. The selective σ1 receptor agonist PRE-084 completely reversed this effect. Four thioamide H2S-σ1 receptor hybrids (5a8a) and their amide derivatives (5b8b) were synthesized. Compound 7a (AD164) robustly released H2S and showed selectivity for σ1 receptor over σ2 and opioid receptors. This compound induced marked analgesia that was reversed by PRE-084. The amide analogue 7b (AD163) showed only minimal analgesia. Further studies showed that 7a exhibited negligible acute toxicity, together with a favorable pharmacokinetic profile. To the best of our knowledge, compound 7a is the first dual-acting ligand with simultaneous H2S-release and σ1 antagonistic activities.
TARGETING IMMUNE-DRIVEN OPIOID ANALGESIA BY SIGMA-1 RECEPTORS: OPENING THE DOOR TO NOVEL PERSPECTIVES FOR THE ANALGESIC USE OF SIGMA-1 ANTAGONISTSTejada, Miguel ÁngelMontilla-García, ÁngelesGonzález Cano, RafaelBravo Caparrós, InmaculadaRuiz Cantero, María del CarmenNieto López, Francisco RafaelCobos del Moral, Enrique Joséhttps://hdl.handle.net/10481/671182022-03-11T10:44:26ZTARGETING IMMUNE-DRIVEN OPIOID ANALGESIA BY SIGMA-1 RECEPTORS: OPENING THE DOOR TO NOVEL PERSPECTIVES FOR THE ANALGESIC USE OF SIGMA-1 ANTAGONISTS
Tejada, Miguel Ángel; Montilla-García, Ángeles; González Cano, Rafael; Bravo Caparrós, Inmaculada; Ruiz Cantero, María del Carmen; Nieto López, Francisco Rafael; Cobos del Moral, Enrique José
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 search for translational pain outcomes to refine analgesic development: Where did we come from and where are we going?González Cano, RafaelMontilla-García, ÁngelesRuiz Cantero, María del CarmenBravo Caparrós, InmaculadaTejada, Miguel ÁngelNieto López, Francisco RafaelCobos del Moral, Enrique Joséhttps://hdl.handle.net/10481/670892022-03-11T10:45:21ZThe search for translational pain outcomes to refine analgesic development: Where did we come from and where are we going?
González Cano, Rafael; Montilla-García, Ángeles; Ruiz Cantero, María del Carmen; Bravo Caparrós, Inmaculada; Tejada, Miguel Ángel; Nieto López, Francisco Rafael; Cobos del Moral, Enrique José
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.
Sigma-1 receptors control neuropathic pain and macrophage infiltration into the dorsal root ganglion after peripheral nerve injuryBravo Caparrós, InmaculadaRuiz Cantero, María del CarmenPerazzoli, GloriaCronin, SFJVela, José MiguelHamed, MFPenninger, JMBaeyens Cabrera, José ManuelCobos del Moral, Enrique JoséNieto López, Francisco Rafaelhttps://hdl.handle.net/10481/670882021-10-07T09:16:20ZSigma-1 receptors control neuropathic pain and macrophage infiltration into the dorsal root ganglion after peripheral nerve injury
Bravo Caparrós, Inmaculada; Ruiz Cantero, María del Carmen; Perazzoli, Gloria; Cronin, SFJ; Vela, José Miguel; Hamed, MF; Penninger, JM; Baeyens Cabrera, José Manuel; Cobos del Moral, Enrique José; Nieto López, Francisco Rafael
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