Background: Sigma-1 receptors (σ1Rs) have immunomodulatory properties and have been shown to modulate gene expression of several proteins related to inflammation. Indeed, σ1R modulation has been suggested to be potentially useful in pathologies where pro-inflammatory cytokines are involved. Here we assessed the potential implication of σ1Rs on colitis using a murine model knockout for σ1Rs. Methods: Adult CD-1 male wild type (WT) and σ1R knockout mice (σ1R KO) were used. Colitis was induced by exposure to a 3% solution of dextran sodium sulfate (DSS) during a 5-day period, followed by a 3-day recovery. Body weight and clinical signs were assessed on a daily basis. At termination, colonic inflammation was assessed macro and microscopically (Stress 2008,11:348–62). Colonic expression of pro- (Interferon -INF-, IL-1, IL-6, IL-18 and IL-12p40) and anti-inflammatory cytokines (IL-10) was also determined (RT-qPCR). Results: During colitis induction, body weight loss and clinical signs were attenuated in σ1R KO vs. WT animals. At necropsy, colonic inflammatory score, changes in colon length and relative weight and colonic histopathological scores were also attenuated in σ1R KO mice (Table 1). Improvement in histopathological scores was due mainly to a reduction in submucosal edema. Basal expression of cytokines was similar in WT and σ1R KO mice, except for IL-12p40 which was up-regulated by 4-fold in σ1R KO mice (p<0.05 vs. WT). During colitis, INF, IL-1 and IL-6 were up-regulated in WT mice (all p<0.05 vs. non-inflamed WT), while only minor expression changes were observed in KO animals (all p>0.05 vs. non-inflamed σ1R KO mice). IL-12p40 showed a selective down-regulation in colitic σ1R KO mice while IL-18 showed minor, non-significant, changes. Regardless the phenotype considered, no changes in IL-10 expression were detected. Expression of σ1Rs was detected in the colon of WT mice, but not in KO animals. In WT mice, σ1R expression was reduced by 28% (p<0.05) during colitis. Table 1 Data are mean ± SEM, n=12–13 animals per group. *p<0.05 vs. respective water-treated group; #p<0.05 vs. WT-DSS group. Conclusions: Lack of functional σ1Rs resulted in an attenuated inflammatory and immune response in the DDS-induced colitis model in mice. These results indicate that σ1Rs are implicated in the modulation of intestinal inflammation. Antagonism of σ1Rs might represent a pharmacological approach for the treatment of intestinal inflammation.

Background: Intestinal inflammation is associated to both visceral and somatic hypersensitivity. Several studies show that sigma-1 receptors (σ1Rs) are implicated in pain and pain sensitization. We assessed the role of σ1Rs on colitis-associated changes in somatic and visceral sensitivity, using a murine model knockout for σ1Rs. Methods: Adult CD-1 male wild type (WT) and σ1R knockout mice (σ1R KO) were used. Colitis was induced by exposure to a 3% solution of dextran sodium sulfate (DSS) during a 5-day period (experimental days 0 to 5), followed by a 2-day recovery. A von Frey test was used to assess changes in somatic (plantar withdrawal response) and visceral mechanosensitivity (abdominal withdrawal response). Changes in mechanosensitivity were assessed before (experimental day −1), during (experimental day 3) and after colitis induction (experimental day 7). At termination, colonic expression (RT-qPCR) of several receptors involved in visceral sensitivity, including cannabinoid receptors (CB1, CB2) and μ-opioid receptor (MOR), was assessed. Results: σ1R KO mice showed attenuated clinical signs and colonic inflammation as assessed macro and microscopically. Somatic and visceral mechanosensitivity was similar in WT and σ1R KO mice before the induction of colitis (Table 1). In WT mice colitis was associated to a time-related development of somatic and visceral mechanical hypersensitivity (Table). In σ1R KO neither somatic nor visceral mechanical sensitivity was altered during inflammation (Table). Basal expression of CB1 and MOR was similar in WT and σ1R KO mice, while CB2 was up-regulated in σ1R KO mice. Regardless the phenotype considered, CB1 and MOR were down-regulated during colitis, while no changes in CB2 expression were observed. Table 1. Data are mean ± SEM, n=6–8 per group. *p<0.05 vs. day −1. Conclusions: Intestinal inflammation-associated visceral and somatic hypersensitivity was absent in σ1R KO mice, thus indicating that σ1Rs are involved in pain sensitization. Antagonism of σ1Rs might represent an attractive pharmacological approach for the treatment of visceral and somatic hypersensitivity.

BACKGROUND AND PURPOSE The sigma‐1 (σ 1 ) receptor is a ligand‐regulated molecular chaperone that has been involved in pain, but there is limited understanding of the actions associated with its pharmacological modulation. Indeed, the selectivity and pharmacological properties of σ 1 receptor ligands used as pharmacological tools are unclear and the demonstration that σ 1 receptor antagonists have efficacy in reversing central sensitization‐related pain sensitivity is still missing. EXPERIMENTAL APPROACH The pharmacological properties of a novel σ 1 receptor antagonist (S1RA) were first characterized. S1RA was then used to investigate the effect of pharmacological antagonism of σ 1 receptors on in vivo nociception in sensitizing conditions and on in vitro spinal cord sensitization in mice. Drug levels and autoradiographic, ex vivo binding for σ 1 receptor occupancy were measured to substantiate behavioural data. KEY RESULTS Formalin‐induced nociception (both phases), capsaicin‐induced mechanical hypersensitivity and sciatic nerve injury‐induced mechanical and thermal hypersensitivity were dose‐dependently inhibited by systemic administration of S1RA. Occupancy of σ 1 receptors in the CNS was significantly correlated with the antinociceptive effects. No pharmacodynamic tolerance to the antiallodynic and antihyperalgesic effect developed following repeated administration of S1RA to nerve‐injured mice. As a mechanistic correlate, electrophysiological recordings demonstrated that pharmacological antagonism of σ 1 receptors attenuated the wind‐up responses in spinal cords sensitized by repetitive nociceptive stimulation. CONCLUSIONS AND IMPLICATIONS These findings contribute to evidence identifying the σ 1 receptor as a modulator of activity‐induced spinal sensitization and pain hypersensitivity, and suggest σ 1 receptor antagonists as potential novel treatments for neuropathic pain.

The increasing global prevalence of obesity unequivocally demonstrates that neither behavioural (diet and exercise) nor pharmacological approaches to this health problem are working. In this area of high unmet clinical need, the 5-HT6 receptor has generated enormous interest amongst academic and pharmaceutical industry scientists as a molecular target for the development of a new generation of safe and more effective anti-obesity drugs. In this review, we have described the major developments that have occurred in the fields of the medicinal chemistry and pharmacology of 5-HT6 ligands, with particular emphasis on their potential application as novel anti-obesity drugs. The last 5 years have witnessed an increasing understanding of the 5-HT6 receptor and its structural requirements that has produced an explosion in the number and diversity of novel, highly selective 5-HT6 receptor agonists, partial agonists and antagonists that have been designed and synthesized. In animal models, 5-HT6 receptor ligands of all functional types have been shown to decrease food intake when given acutely and chronically, to evoke profound and sustained weight-loss in obese animals, and concomitantly to improve a number of cardio-metabolic risk factors. Comparator studies in obese animal models, which are highly predictive of clinical outcomes, indicate that 5-HT6 ligands may have the potential to be more efficacious in the treatment of obesity than the current generation of anti-obesity drugs.

Although the 5-hydroxytryptamine(6) (5-HT(6)) receptor was discovered only recently, its almost exclusive distribution in the brain makes it a promising, novel, target for central nervous system (CNS)-mediated diseases such as Alzheimer's disease (cognitive function), schizophrenia, anxiety and obesity. In the past few years a significant research interest has advanced the understanding of the functional roles and the pharmacophore requirements of this receptor. Two 5-HT(6) receptor antagonists have already entered Phase II clinical trials for the enhancement of cognitive function. Since the first discovery of selective ligands for the 5-HT(6) receptor by HTS in 1998, several medicinal-chemistry-driven approaches have delivered highly selective lead structures with well-defined functionalities, starting from either the endogenous ligand 5-HT or the chemical structures identified by HTS. The concept of 'scaffold hopping' has been employed to expand the variability of the available chemical scaffolds and to generate patentable ligands. Supported by pharmacophore models, which have been established recently, the binding and functionality (structure-activity relationships) of the lead structures have been optimized further.

Based on a medicinal chemistry guided hypothetical pharmacophore model, novel series of indolyl sulfonamides have been designed and prepared as selective and high-affinity serotonin 5-HT(6) receptor ligands. Furthermore, based on a screening approach of a discovery library, a series of benzoxazinepiperidinyl sulfonamides were identified as selective 5-HT(6) ligands. Many of the compounds described in this paper possess excellent affinities, displaying pK(i) values greater than 8 (some even >9) and high selectivities against a wide range (>50) of other CNS relevant receptors. First, structure-affinity relationships of these ligands are discussed. In terms of functionality, high-affinity antagonists, as well as agonists and even partial agonists, were prepared. Compounds 19c and 19g represent the highest-affinity 5-HT(6) agonists ever reported in the literature. These valuable tool compounds should allow for the detailed study of the role of the 5-HT(6) receptor in relevant animal models of disorders such as cognition deficits, depression, anxiety, or obesity.

Sigma (sigma) sites are a type of nonopiate receptor whose role has been associated with several behaviours, including anxiety, depression, analgesia, learning processes and psychosis. Although there are several known sigma receptor types, only the type I receptor (sigma 1) has been cloned. To uncover the in vivo relevance of sigma-receptors, we have generated knockout mice for sigma 1. Despite the broad expression pattern found for the sigma 1-gene, homozygous mutant mice are viable, fertile and do not display any overt phenotype, compared with their wild-type litter-mates, in mixed genetic backgrounds. However, a significant decrease in the hypermotility response has been measured in knockout mice upon challenge with (+)SKF-10 047, in agreement with the involvement of sigma 1-receptors in the induction of psychostimulant actions. The activity of sigma 2-receptors seems to be unaffected in sigma 1-mutant mice. These knockout mice could contribute to better understand the in vivo role of sigma-receptors.

Pigeons were trained to respond on a fixed-interval 3-min (FI 3 min) schedule of food reinforcement. During each 1-hr session responses on a second response key produce a timeout from the FI schedule. mThe food reinforcement schedule maintained characteristic FI responding. The escape-timeout responses occurred during the period of low response rates following reinforcement. Morphine (0.25, 0.5, 1.0 mg/kg) produced dose-related rate-dependent decreases in mean fixed-interval response rates. As morphine dose increased, there was an increased tendency for the rates within the interval to converge from a variety of predrug rates to a common, low rate of responding. The effect of morphine on the schedule-induced escape responses was to increase the mean number of escapes at doses of 0.25–0.5 mg/kg and to decrease the escapes at the highest dose of 1.0 mg/kg. The mean duration of the escape-timeouts was increased by the 3 doses of the drug, with the longest durations occurring at the 0.5 mg/kg dose. There was a great deal of variability between subjects on these measures and the dose effects did not reach statistical significance. The present study extends the analysis of drug effects on schedule-induced escape to fixed-interval-induced escape responding and includes the drug morphine.

s: Abstract of a Workshop on Schizophrenia, a joint meeting of the European Behavioural Pharmacological Society and the Dutch Interdisciplinary Socity for Biological Psychiatry, Amsterdam, 21–24 June 2000

CNS Drug ReviewsVolume 4, Issue 3 p. 201-224 Free Access E-5842: A New Potent and Preferential Sigma Ligand. Preclinical Pharmacological Profile X. Guitart*, Corresponding Author X. Guitart* Neuropharmacology Department, Research Center, Laboratorio Esteve S. A., Barcelona, SpainDr. X. Guitart, Dept. Neuropharmacology, Research Center, Laboratorio Esteve S. A., Verge de Montserrat, 221. Barcelona, E-08041, Spain. Fax: +34-93-450-1611.Search for more papers by this authorX. Codony, X. Codony Neuropharmacology Department, Research Center, Laboratorio Esteve S. A., Barcelona, SpainSearch for more papers by this authorM. Ballarín, M. Ballarín Neuropharmacology Department, Research Center, Laboratorio Esteve S. A., Barcelona, SpainSearch for more papers by this authorA. Dordal, A. Dordal Neuropharmacology Department, Research Center, Laboratorio Esteve S. A., Barcelona, SpainSearch for more papers by this authorA. J. Farré, A. J. Farré Neuropharmacology Department, Research Center, Laboratorio Esteve S. A., Barcelona, SpainSearch for more papers by this author X. Guitart*, Corresponding Author X. Guitart* Neuropharmacology Department, Research Center, Laboratorio Esteve S. A., Barcelona, SpainDr. X. Guitart, Dept. Neuropharmacology, Research Center, Laboratorio Esteve S. A., Verge de Montserrat, 221. Barcelona, E-08041, Spain. Fax: +34-93-450-1611.Search for more papers by this authorX. Codony, X. Codony Neuropharmacology Department, Research Center, Laboratorio Esteve S. A., Barcelona, SpainSearch for more papers by this authorM. Ballarín, M. Ballarín Neuropharmacology Department, Research Center, Laboratorio Esteve S. A., Barcelona, SpainSearch for more papers by this authorA. Dordal, A. Dordal Neuropharmacology Department, Research Center, Laboratorio Esteve S. A., Barcelona, SpainSearch for more papers by this authorA. J. Farré, A. J. Farré Neuropharmacology Department, Research Center, Laboratorio Esteve S. A., Barcelona, SpainSearch for more papers by this author First published: 07 June 2006 https://doi.org/10.1111/j.1527-3458.1998.tb00065.xCitations: 21AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume4, Issue3September 1998Pages 201-224 ReferencesRelatedInformation