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DOP088 Somatic and visceral hypersensitivity associated to acute intestinal inflammation are absent in sigma 1 receptor knockout mice

Lόpez-Estévez S.*1, Gris G.2, de la Puente B.2, Codony X.2, Merlos M.2, Martínez V.1

1Universitat Autònoma de Barcelona, Cell Biology, Physiology and Immumology, Bellaterra, Spain 2Esteve, Department of Pharmacology, Drug Discovery & Preclinical Development, Barcelona, Spain

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.

Conclusion

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.