tegaserod and Pain

Tegaserod reduces the symptoms associated with irritable bowel syndrome, and anti-nociceptive effects have been demonstrated in animals. Its effect on the rectal sensitivity in humans has not been delineated clearly.. To evaluate the action of tegaserod on rectal sensitivity in response to distension by means of a reflexological technique based on electrophysiological recordings of the RIII nociceptive reflex.. A randomized, double-blind, placebo-controlled study, performed in 20 healthy women, quantified the effects of slow or rapid rectal distensions on the RIII reflex at baseline and on day 8 following treatment with either placebo or tegaserod (6 mg b.d.).. At baseline, slow distensions performed up to the pain threshold induced gradual inhibitions of the RIII reflex. On day 8, these inhibitory effects were significantly reduced in the tegaserod group, but not in the placebo group (P = 0.0001). The effects of rapid distensions were not significantly modified by tegaserod or placebo. The intensity of subjective pain perception and rectal compliance were not altered by either treatment.. These results suggest that tegaserod reduces the sensitivity to rectal distension in healthy subjects and interacts with the processing of sensory visceral information.

Topics: Adult; Double-Blind Method; Female; Humans; Indoles; Middle Aged; Pain; Pressure; Rectum; Reflex; Sensitivity and Specificity; Sensory Thresholds; Serotonin Receptor Agonists

We report the discovery and initial characterization of a novel class of selective NPFF2 agonists. HTS screening using R-SAT, a whole cell based functional assay, identified a class of aryliminoguanidines as NPFF1 and NPFF2 ligands. Subsequent optimization led to molecules exhibiting selective NPFF2 agonistic activity. Systemic administration showed that selective NPFF2 agonists (1 and 3) are active in various pain models in vivo, whereas administration of a nonselective NPFF1 and NPFF2 agonist (9) increases sensitivity to noxious and non-noxious stimuli.

Topics: Analgesics; Animals; Carrageenan; Guanidines; Humans; In Vitro Techniques; Inflammation; Microsomes, Liver; Pain; Pain Measurement; Peripheral Nervous System Diseases; Rats; Receptors, Neuropeptide

To establish a model of chronic visceral hypersensitivity in rats and to investigate the effect of tegaserod, a partial 5-hydroxytryptamine-4 receptor agonist, on visceral hypersensitivity.. Neonate Sprague-Dawley rats at 8-21 days after birth underwent colorectal distension once daily. Adult rats aged 8-10 postnatal weeks underwent colorectal distension and the abdominal withdrawal reflex (AWR) during the distension was determined. The AWR score was recorded before and after intraperitoneal administration of either tegaserod (treatment group: 0.3 mg/kg) or vehicle (control group).. Changes in the AWR score were dependent on the pressure intensity of the colorectal distension (P < 0.01). At pressures of 40, 60 and 80 mmHg, the AWR scores in the model rats with visceral hypersensitivity were significantly higher than those recorded in the control group (1.95 +/- 0.16 vs 1.35 +/- 0.15, 2.82 +/- 0.12 vs 2.17 +/- 0.13, 3.20 +/- 0.14 vs 2.59 +/- 0.14, P < 0.01). Compared with the controls, tegaserod significantly decreased the AWR scores at the distension pressures of 40, 60 and 80 mmHg (1.95 +/- 0.50 vs 1.32 +/- 0.55, 3.05 +/- 0.48 vs 2.32 +/- 0.54, 3.25 +/- 0.63 vs 2.77 +/- 0.51, P < 0.05).. Adult rats can develop chronic visceral hypersensitivity after transient colorectal mechanical irritation during their postnatal period. Tegaserod increases the pain threshold to noxious stimuli, suggesting an antinociceptive property in its effect on visceral hypersensitivity.

Topics: Animals; Animals, Newborn; Colonic Diseases; Disease Models, Animal; Female; Humans; Indoles; Irritable Bowel Syndrome; Male; Pain; Rats; Rats, Sprague-Dawley; Rectal Diseases; Serotonin Receptor Agonists

To investigate the mechanisms of tegaserod, a partial 5-HT4 agonist, in reducing visceral sensitivity by observing Fos, substance P (SP) and calcitonin gene-related peptide (CGRP) expression in the lumbarsacral spinal cord induced by colonic inflammation in rats.. Twenty-four male rats with colonic inflammation induced by intraluminal instillation of trinitrobenzenesulfonic acid (TNBS) were divided into 3 groups. Treatment group 1: intra-gastric administration of tegaserod, 2 mg/kg.d; Treatment group 2: intra-gastric administration of tegaserod, 1 mg/kg.d;. intra-gastric administration of saline, 2.0 mL/d. After 7 d of intra-gastric administration, lumbarsacral spinal cord was removed and processed for Fos, SP and CGRP immunohistochemistry.. In rats of the control group, the majority of Fos labeled neurons was localized in deeper laminae of the lumbarsacral spinal cord (L(5)-S(1)). SP and CGRP were primarily expressed in the superficial laminae of the spinal cord after TNBS injection. Intra-gastric administration of tegaserod (2 mg/kg.d) resulted in a significant decrease of Fos labeled neurons (22.0+/-7.7) and SP density (12.5+/-1.4) in the dorsal horn in the lumbarsacral spinal cord compared to those of the control group (62.2+/-18.9, 35.9+/-8.9, P<0.05). However, CGRP content in dorsal horn did not significantly reduce in rats of treatment group 1 (1.2+/-1.1) compared to that of the control group (2.8+/-2.4, P>0.05). Neither Fos expression nor SP or CGRP density in the dorsal horn significantly declined in rats of treatment group 2 compared to those of the control group (P>0.05).. Tegaserod can significantly reduce Fos labeled neurons in the lumbarsacral spinal cord induced by colonic inflammation. Tegaserod may reduce visceral sensitivity by inhibiting SP expression in the dorsal horn of spinal cord.

Topics: Animals; Calcitonin Gene-Related Peptide; Colitis; Disease Models, Animal; Gastrointestinal Agents; Indoles; Male; Pain; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Spinal Cord; Substance P; Visceral Afferents