Fedotozine, a kappa‐opioid agonist, prevents spinal and supra‐spinal Fos expression induced by a noxious visceral stimulus in the rat

Abstract

Fedotozine, a kappa opioid agonist, reverses digestive ileus caused by acetic acid (AA)-induced visceral pain in rats. The aims of this study were: to map, in conscious rats, central pathways activated by AA using Fos as a marker of neuronal activation; to characterize primary afferent fibres involved in this activation; and to investigate the effect of fedotozine on AA-induced Fos expression. AA (0.6%; 10 mL kg-1) was injected i.p. in conscious rats either untreated; pretreated 14 days before with capsaicin; pretreated 20 min previously with fedotozine; or pretreated 2 h prior to fedotozine with the kappa-antagonist nor-binaltorphimine (nor-BNI). Controls received the vehicle alone. 60 min after injection of AA, rats were processed for Fos immunohistochemistry. Visceral pain was assessed by counting abdominal cramps. AA induced Fos in the thoraco-lumbar spinal cord (laminae I, V, VII and X) and numerous brain structures such as the nucleus tractus solitarius, and paraventricular nucleus (PVN) of the hypothalamus, whereas almost no Fos labelling was observed in controls. Capsaicin pretreatment blocked AA-induced Fos in all structures tested. Fedotozine significantly decreased AA-induced abdominal cramps and Fos immunoreactivity in the spinal cord and PVN, this effect being reversed by nor-BNI pretreatment. AA induces Fos in the spinal cord and numerous brain nucuei, some of which are involved in the control of digestive motility in rats. This effect is mediated through capsaicin-sensitive afferent fibres and prevented by fedotozine most likely through a peripheral action on visceral afferents.

Evidence That Hydrogen Sulfide Exerts Antinociceptive Effects in the Gastrointestinal Tract by Activating KATP Channels

“…Because induction of c-FOS expression is widely used as an index of nociception and activation of afferent pathways (Bonaz et al, 2000), our data support the notion that H 2 S functions as a neuromodulator that participates in the inhibitory modulation of visceral nociception in the CNS.…”

5-Amino-2-hydroxybenzoic Acid 4-(5-Thioxo-5H-[1,2]dithiol-3yl)-phenyl Ester (ATB-429), a Hydrogen Sulfide-Releasing Derivative of Mesalamine, Exerts Antinociceptive Effects in a Model of Postinflammatory Hypersensitivity

“…In animal models of acute (Bonaz et al, 2000) and chronic (Julia et al, 1995) inflammation, abnormal pain responses to CRD have been observed, demonstrating that inflammation induces both hyperalgesia and allodynia that persist when local inflammation is partially or totally resolved. Human studies in patients with ulcerative colitis and Crohn's disease (Bernstein et al, 1996;Chang et al, 2000) and IBS (Collins et al, 2001) have confirmed that colonic inflammation modulates colonic neural afferents.…”

Effect of nor-trimebutine on neuronal activation induced by a noxious stimulus or an acute colonic inflammation in the rat

“…Fos, the protein product of the immediate early gene c-fos is a sensitive marker of neuronal activation classically used to localize 3 V. Sinniger et al spinal cord neurons responsive to acute stimuli of somatic or visceral origin (Menetrey et al, 1989;Hunt et al, 1987;Herdegen et al, 1991;Traub et al, 1992Traub et al, , 1993. Using the model of somatovisceral pain, we have previously shown that, fedotozine, a kappa-opioid receptor agonist known to improve abdominal symptoms in IBS patients (Dapoigny et al, 1995;Delvaux et al, 1999), has an antinociceptive effect and prevents AA-induced Fos expression in the thoraco-lumbar spinal cord in rats through a peripheral action on visceral afferents (Bonaz et al, 2000).…”

“…Somato-visceral pain was assessed by counting abdominal contractions (Koster et al, 1959;Giamberardino et al, 1995;Bonaz et al, 2000) for 60 minutes, by periods of 10 min, following the ip injection of AA, classically described as the writhing test (Koster et al, 1959). Abdominal contractions consisted of the contraction of the flank muscles associated with inward movements of the hindlimb or with whole body stretching (Giamberardino et al, 1995).…”

“…Somato-visceral pain was induced in conscious rats (n=5) with ip injection of 0.6% AA (10 ml/kg) in the right lower quadrant of the abdomen as previously described (Bonaz et al, 2000).…”