Role of sigma-1 ( σ 1 ) receptors in capsaicin-induced visceral pain in mice.

R. González-Cano1, C.M. Cendán1, M. Tejada-Giraldez1, M. Merlos2, J.M. Baeyens1. 1Faculty of Medicine, 18012 Granada, Department of Pharmacology and Institute of Neuroscience, Spain, 2Laboratorios Dr. Esteve S.A., 08041 Barcelona, Drug Discovery and Preclinical Development, Spain

Visceral pain is the most frequent type of pathological pain and one of the main reasons for patients to seek medical assistance. The role of sigma-1 (σ1) receptors in pain control has been well established in different somatic pain models, but it is almost unexplored in visceral pain. To test this possibility we performed studies on the intracolonic-capsaicin model in mice. Firstly, we compared the responses induced by capsaicin in naïve wild-type (WT) and σ1 receptor knockout (σ1-KO) mice. Secondly, we evaluated the effect of several selective σ1 receptor antagonists (BD-1063, S1RA and NE-100) and control drugs (morphine and ketoprofen) in both kinds of mice in this model.

WT and σ1-KO female CD-1 (24-30 g) mice were used. For behavioral testing, 0.05 ml of vehicle or capsaicin (0.01-1%) was administered by inserting a fine cannula into the colon via the anus and mice were placed on a raised grid. Visceral pain-related behaviors (licking, stretching and contractions of the abdomen) were immediately counted for 20 min after intracolonic (i.cl.) administration of capsaicin. Referred mechanical hyperalgesia was quantified, 20 min after the i.cl. instillation of capsaicin, by measuring the response to the stimulus with von Frey filaments: immediate licking or scratching of site of application, a sharp retraction of abdomen and/or jumping. The calibrated von Frey monofilaments (0.02-2 g; i.e. 0.19-19.6 mN) were applied to the abdomen and threshold for response was measured using the up-down paradigm. Testing was initiated with the 0.4 g filament. The experimental protocol was approved by the University of Granada Research Ethics Committee. The number of behaviors and mechanical thresholds were compared across experimental groups with one-way or two-way analysis of variance (ANOVA) followed by the Bonferroni test.

The i.cl. administration of capsaicin induced dose-dependent visceral pain behaviors and referred hyperalgesia (significant reduction in threshold to von Frey filaments) in both WT and σ1-KO mice. The maximum number of pain-related behaviors induced by capsaicin in σ1-KO mice (21.72±4.17) was the half (p<0.01) of those observed in WT (45.64±4.17), but there were no significant differences in the response to von Frey filaments between both types of animals (0.54±0.08 and 0.52±0.05 g in WT and KO, respectively; p>0.05). The subcutaneous (s.c.) administration (30 min before i.cl. capsaicin) of the selective σ1 receptor antagonists BD-1063 (16-64 mg/kg), S1RA (32-128 mg/kg) and NE-100 (8-64 mg/kg), dose-dependently inhibited the behavioral responses and the referred hyperalgesia in WT mice (p<0.01 with the highest doses tested). In contrast, these σ1 receptor antagonists did not affect pain behaviors and referred hyperalgesia in σ1-KO mice (p>0.05). The s.c. injection of morphine (2-16 mg/kg) produced a dose-dependent inhibition of capsaicin-induced visceral pain in WT and σ1-KO mice whereas ketoprofen (32-128 mg/kg) had not effect at any dose tested in any type of mice.

These results suggest that σ1 receptors play a role in the mechanisms underlying capsaicin-induced visceral pain.

Supported by MEC (project SAF2010-15343), Junta de Andalucía (CTS-109 group), MEC-FPU (RGC) and University of Granada (CMC)