Downregulation of mesenteric afferent sensitivity following long-term systemic treatment of vincristine in mice

Abstract

Aims: Gastrointestinal paresthesia and dysmotility are common side effects of vincristine (VCR) chemotherapy, which have become one of the factors for dose reduction, therapy delay or discontinuation. However, the mechanism is not entirely clear, whether it is related to autonomic nerves injury remains unknown. Therefore, we aimed to study whether VCR-induced gastrointestinal toxicity is related to changes in mesenteric afferent activity.

Methods: The effects of a single VCR stimulation and long-term systemic VCR treatment on mesenteric afferent activity were investigated by directly recording mesenteric afferent discharge in vitro.

Results: Our results showed that a single VCR (0.001-1 μmol/L) stimulation obviously increased the spontaneous, chemically evoked and mechanically evoked discharge of jejunal and colonic mesenteric afferents. This kind of hypersensitivity of VCR could be blocked by capsazepine, a transient receptor potential vanilloid 1 (TRPV1) antagonist. For the mice treated with VCR (0.1 mg/kg/d, i.p.) for 14 days, the abdominal withdrawal reflex and writhing response scores were reduced. Meanwhile, the spontaneous discharge of colonic mesenteric afferents and the afferent response to VCR was downregulated, and the afferent sensitivity to chemical and mechanical stimulation was reduced. Moreover, the expression of TRPV1 in colon was decreased.

Conclusions: These results suggest that the direct stimulation by VCR increases the mesenteric afferent sensitivity by activating TRPV1, which may be the reason of VCR-induced abdominal pain; the long-term systemic treatment of VCR decreases mesenteric afferent sensitivity by reducing TRPV1, which may be the reason of VCR-induced constipation.

Keywords: Hypersensitivity; Hyposensitivity; Mesenteric afferent nerves; TRPV1; Vincristine.