Drug Discovery and Preclinical Development

Barcelona, Spain

Drug Discovery and Preclinical Development

Barcelona, Spain
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Rodriguez-Munoz M.,Instituto Cajal | Sanchez-Blazquez P.,Instituto Cajal | Herrero-Labrador R.,Instituto Cajal | Martinez-Murillo R.,Instituto Cajal | And 3 more authors.
Antioxidants and Redox Signaling | Year: 2015

Aims: The in vivo pharmacology of the sigma 1 receptor (σ1R) is certainly complex; however, σ1R antagonists are of therapeutic interest, because they enhance mu-opioid receptor (MOR)-mediated antinociception and reduce neuropathic pain. Thus, we investigated whether the σ1R is involved in the negative control that glutamate N-methyl-d-aspartate acid receptors (NMDARs) exert on opioid antinociception. Results: The MOR C terminus carries the histidine triad nucleotide-binding protein 1 (HINT1) coupled to the regulator of G-protein signaling RGSZ2-neural nitric oxide synthase assembly. Activated MORs stimulate the production of nitric oxide (NO), and the redox zinc switch RGSZ2 converts this signal into free zinc ions that are required to recruit the redox sensor PKCγ to HINT1 proteins. Then, PKCγ impairs HINT1-RGSZ2 association and enables σ1R-NR1 interaction with MOR-HINT1 complexes to restrain opioid signaling. The inhibition of NOS or the absence of σ1Rs prevents HINT1-PKCγ interaction, and MOR-NMDAR cross-regulation fails. The σ1R antagonists transitorily remove the binding of σ1Rs to NR1 subunits, facilitate the entrance of negative regulators of NMDARs, likely Ca2+-CaM, and prevent NR1 interaction with HINT1, thereby impairing the negative feedback of glutamate on opioid analgesia. Innovation: A redox-regulated process situates MOR signaling under NMDAR control, and in this context, the σ1R binds to the cytosolic C terminal region of the NMDAR NR1 subunit. Conclusion: The σ1R antagonists enhance opioid analgesia in naïve mice by releasing MORs from the negative influence of NMDARs, and they also reset antinociception in morphine tolerant animals. Moreover, σ1R antagonists alleviate neuropathic pain, probably by driving the inhibition of up-regulated NMDARs. © Copyright 2015, Mary Ann Liebert, Inc.


Gomez-Soler M.,Lhospitalet Of Llobregat | Fernandez-Duenas V.,Lhospitalet Of Llobregat | Portillo-Salido E.,Drug Discovery and Preclinical Development | Perez P.,Drug Discovery and Preclinical Development | And 4 more authors.
Journal of Medicinal Chemistry | Year: 2014

We have developed a novel methodology for monitoring the σ1 receptor activation switch in living cells. Our assay uncovered the intrinsic nature of σ1 receptor ligands by recording the ligand-mediated conformational changes of this chaperone protein. The change triggered by each ligand correlated well with its ability to attenuate formalin induced nociception in an animal model of pain. This tool may assist in predicting the antinociceptive efficacy of σ1 receptor ligands. © 2013 American Chemical Society.


Nieto F.R.,University of Granada | Cendan C.M.,University of Granada | Sanchez-Fernandez C.,University of Granada | Cobos E.J.,University of Granada | And 5 more authors.
Journal of Pain | Year: 2012

Sigma-1 (σ1) receptors play a role in different types of pain and in central sensitization mechanisms; however, it is unknown whether they are involved in chemotherapy-induced neuropathic pain. We compared the ability of paclitaxel to induce cold (acetone test) and mechanical (electronic Von Frey test) allodynia in wild-type (WT) and σ1 receptor knockout (σ1-KO) mice. We also tested the effect on paclitaxel-induced painful neuropathy of BD-1063 (16-64 mg/kg, subcutaneously) and S1RA (32-128 mg/kg, subcutaneously), 2 selective σ1 receptor antagonists that bind to the σ1 receptor with high affinity and competitively. The responses to cold and mechanical stimuli were similar in WT and σ1-KO mice not treated with paclitaxel; however, treatment with paclitaxel (2 mg/kg, intraperitoneally, once per day during 5 consecutive days) produced cold and mechanical allodynia and an increase in spinal cord diphosphorylated extracellular signal-regulated kinase (pERK) in WT but not in σ1-KO mice. The administration of BD-1063 or S1RA 30 minutes before each paclitaxel dose prevented the development of cold and mechanical allodynia in WT mice. Moreover, the acute administration of both σ1 receptor antagonists dose dependently reversed both types of paclitaxel-induced allodynia after they had fully developed. These results suggest that σ1 receptors play a key role in paclitaxel-induced painful neuropathy. Perspective: Antagonists of the σ1 receptor may have therapeutic value for the treatment and/or prevention of paclitaxel-induced neuropathic pain. This possibility is especially interesting in the context of chemotherapy-induced neuropathy, where the onset of nerve damage is predictable and preventive treatment could be administered. © 2012 by the American Pain Society.


Sanchez-Blazquez P.,Cajal Institute | Rodriguez-Munoz M.,Cajal Institute | Herrero-Labrador R.,Cajal Institute | Burgueno J.,Drug Discovery and Preclinical Development | And 2 more authors.
International Journal of Neuropsychopharmacology | Year: 2014

Through the cannabinoid receptor 1 (CB1), the endocannabinoid system plays a physiological role in maintaining the activity of glutamate N-methyl-D-aspartate (NMDA) receptor within harmless limits. The influence of cannabinoids must be proportional to the stimulus in order to prevent NMDAR overactivation or exaggerated hypofunction that may precipitate symptoms of psychosis. In this framework, the recently reported association of CB1s with NMDARs, which mediates the reduction of cannabinoid analgesia promoted by NMDAR antagonism, could also support the precipitation of schizophrenia brought about by the abuse of smoked cannabis, mostly among vulnerable individuals. Accordingly, we have investigated this possibility using neuroprotection and analgesia as reporters of the CB1-NMDAR connection. We found that the Sigma 1 receptor (σ1R) acts as a safety switch, releasing NMDARs from the influence of CB1s and thereby avoiding glutamate hypofunction. In σ1R-/- mice the activity of NMDARs increases and cannot be regulated by cannabinoids, and NMDAR antagonism produces no effect on cannabinoid analgesia. In wild-type mice, ligands of the σ1R did not affect the CB1-NMDAR regulatory association, however, experimental NMDAR hypofunction enabled ó1R antagonists to release NMDARs from the negative control of CB1s. Of the σ1R antagonists tested, their order of activity was: S1RA> BD1047蠑 NE100=BD1063, although SKF10047, PRE-084 and (+)pentazocine were inactive yet able to abolish the effect of S1RA in this paradigm. Thus, the σ1R controls the extent of CB1-NMDAR interaction and its failure might constitute a vulnerability factor for cannabis abuse, potentially precipitating schizophrenia that might otherwise be induced later in time by the endogenous system. © CINP 2014.


Rodriguez-Munoz M.,Laboratory Of Neuropharmacology Instituto Cajal | Sanchez-Blazquez P.,Laboratory Of Neuropharmacology Instituto Cajal | Merlos M.,Drug Discovery and Preclinical Development | Garzon-Nino J.,Laboratory Of Neuropharmacology Instituto Cajal
Oncotarget | Year: 2016

Glutamate is probably the most important excitatory neurotransmitter in the brain. The glutamate N-methyl-D-aspartate receptor (NMDAR) is a calcium-gated channel that coordinates with G protein-coupled receptors (GPCRs) to establish the efficiency of the synaptic transmission. Cross-regulation between these receptors requires the concerted activity of the histidine triad nucleotide-binding protein 1 (HINT1) and of the sigma receptor type 1 (σ1R). Essential brain functions like learning, memory formation and consolidation, mood and behavioral responses to exogenous stimuli depend on the activity of NMDARs. In this biological context, endocannabinoids are released to retain NMDAR activity within physiological limits. The efficacy of such control depends on HINT1/σ1R assisting in the physical coupling between cannabinoid type 1 receptors (CB1Rs) and NMDARs to dampen their activity. Subsequently, the calcium-regulated HINT1/σ1R protein tandem uncouples CB1Rs to prevent NMDAR hypofunction. Thus, early recruitment or a disproportionate cannabinoid induced response can bring about excess dampening of NMDAR activity, impeding its adequate integration with GPCR signaling. Alternatively, this control circuit can apparently be overridden in situations where bursts of NMDAR overactivity provoke convulsive syndromes. In this review we will discuss the possible relevance of the HINT1/σ1R tandem and its use by endocannabinoids to diminish NMDAR activity and their implications in psychosis/schizophrenia, as well as in NMDAR-mediated convulsive episodes.


Vidal-Torres A.,Drug Discovery and Preclinical Development | Carceller A.,Drug Discovery and Preclinical Development | Zamanillo D.,Drug Discovery and Preclinical Development | Merlos M.,Drug Discovery and Preclinical Development | And 2 more authors.
Journal of Pharmacological Sciences | Year: 2012

Measurement of neurotransmitters in the spinal dorsal horn in conscious animals remains a technical challenge. Here we applied concentric microdialysis to measure formalin-induced glutamate (Glu) release in the ipsilateral dorsal horn in conscious, freely-moving rats. Hind paw formalin injection induced flinching nociceptive behaviors accompanied by increased Glu in the dorsal horn (maximum = 294%). Both flinching and Glu increase were prevented by morphine (3 mg/kg, s.c.). Accordingly, concentric microdialysis is a sensitive technique for studying neurochemical modulation induced by pain and analgesics in the spinal dorsal horn of awake rats. Measurement of Glu provides information on modulation of excitatory signals. © 2012 The Japanese Pharmacological Society.


Almansa C.,Drug Discovery and Preclinical Development | Vela J.M.,Drug Discovery and Preclinical Development
Future Medicinal Chemistry | Year: 2014

The sigma-1 receptor (σ1R) is located in areas of the CNS key for pain control and belongs to a unique target class with chaperoning functions over different molecular targets involved in transmission and amplification of nociceptive messages. Preclinical evidence supports a role for σ1R antagonists in the treatment of pain states where hypersensitivity develops as hyperalgesia and allodynia, two common symptoms encountered in neuropathic and other chronic pain conditions. Additionally, σ1R antagonists increase opioid analgesia without increasing opioid-related unwanted effects, which point to their potential use as opioid adjuvant therapy. This review summarizes the structure and function of the σ1R as well as the medicinal chemistry and pharmacological studies directed to the identification of σ1R antagonists for the treatment of pain. © 2014 Future Science Ltd.


Gris G.,Drug Discovery and Preclinical Development | Merlos M.,Drug Discovery and Preclinical Development | Vela J.M.,Drug Discovery and Preclinical Development | Zamanillo D.,Drug Discovery and Preclinical Development | Portillo-Salido E.,Drug Discovery and Preclinical Development
Behavioural Pharmacology | Year: 2014

The therapeutic potential of S1RA (E-52862), a selective sigma-1 receptor (σ1R) antagonist, has been explored in experimental neuropathic pain, but not in inflammatory pain models. The present study investigated the effect of the intraperitoneal administration of S1RA on the hind paw withdrawal response to thermal and mechanical stimulation following an intraplantar injection of carrageenan (CARR) and complete Freund's adjuvant (CFA), which are two well-characterized models of acute and chronic inflammatory pain, respectively. S1RA fully reversed both mechanical [dose of drug that produced half of its maximal response (ED50)=35.9 and 42.1 mg/kg for CARR-induced and CFA-induced pain, respectively] and thermal (ED50=27.9 mg/kg, CARR) hypersensitivity, whereas ibuprofen (CARR, mechanical allodynia) and celecoxib (CARR, thermal hyperalgesia; CFA, mechanical allodynia) failed to reach maximum efficacy. Morphine also showed maximum efficacy in all tests. Unlike celecoxib and ibuprofen, which decreased paw volume significantly, CARR-induced paw oedema was not reduced by S1RA and morphine, thus suggesting that the antinociceptive effect of S1RA does not involve a major anti-inflammatory (antioedema) action. S1RA was devoid of efficacy when administered to σ1R knockout mice, thus suggesting the involvement of σ1R in the antinociceptive effects exerted by S1RA. We conclude that S1RA represents a promising novel analgesic therapy for inflammatory pain. © 2014 Wolters Kluwer Health.


Brenchat A.,Drug Discovery and Preclinical Development
European journal of pain (London, England) | Year: 2012

Several studies have suggested that 5-HT(7) receptors are involved in nociceptive processing but the exact contribution of peripheral versus central 5-HT(7) receptors still needs to be elucidated. In the present study, the respective roles of peripheral and spinal 5-HT(7) receptors in the modulation of mechanical hypersensitivity were investigated under two different experimental pain conditions. In a first set of experiments, the selective 5-HT(7) receptor agonist, E-57431, was systemically, intrathecally or peripherally (intraplantarly) administered to rats sensitized by intraplantar injection of capsaicin. Oral administration of E-57431 (1.25-10 mg/kg) was found to exert a clear-cut dose-dependent reduction of capsaicin-induced mechanical hypersensitivity. Interestingly, intrathecal administration of E-57431 (100 μg) also inhibited mechanical hypersensitivity secondary to capsaicin injection. In contrast, a dose-dependent enhancement of capsaicin-induced mechanical hypersensitivity was observed after local intraplantar injection of E-57431 (0.01-1 μg). In a second set of experiments, E-57431 was systemically or intrathecally administered to rats submitted to neuropathic pain (spared nerve injury model). Significant inhibition of nerve injury-induced mechanical hypersensitivity was found after intraperitoneal (10 mg/kg) as well as intrathecal (100 μg) administration of E-57431 in this chronic pain model. These studies provide evidence that, under sensitizing neurogenic/neuropathic conditions, activation of 5-HT(7) receptors exerts antinociceptive effects at the level of the spinal cord and pronociceptive effects at the periphery. The antinociceptive effect mediated by central 5-HT(7) receptors seems to predominate over the pronociceptive effect at the periphery when a selective 5-HT(7) receptor agonist is systemically administered. © 2011 European Federation of International Association for the Study of Pain Chapters.


Brenchat A.,Drug Discovery and Preclinical Development | Ejarque M.,Drug Discovery and Preclinical Development | Zamanillo D.,Drug Discovery and Preclinical Development | Vela J.M.,Drug Discovery and Preclinical Development | Romero L.,Drug Discovery and Preclinical Development
Journal of Pharmacological Sciences | Year: 2011

Spinal blockade of 5-HT 7 receptors has been reported to inhibit the antinociceptive effect of opioids. In this study, we found that subcutaneous administration of the selective 5-HT 7 receptor agonist E-55888 (10 mg/kg) or the antagonist SB-258719 (5 mg/kg) exerted no effect on the tail-flick test in mice. However, E-55888, but not SB-258719, increased (2.6-fold) the analgesic potency of oral morphine. The potentiating effect exerted by E-55888 was prevented by SB-258719. A pharmacokinetic interaction was discarded as morphine plasma and brain concentrations were not significantly modified when co-administered with E-55888. These results reinforce the involvement of 5-HT 7 receptors in opioid analgesia and point to a potential use of 5-HT 7 receptor agonists as adjuvants of opioid analgesia. © The Japanese Pharmacological Society.

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