Ketamine Analog Methoxetamine Induced Inflammation and Dysfunction of Bladder in Rats.

Peng Wu,Qiang Wang,Qinghui Wu,Jie Zhao,Guihao Zhang,Yang Chen,Junpeng Wang,Jiawei Chen

doi:10.3390/ijms18010117

Abstract

The novel synthetic psychoactive ketamine analog methoxetamine is reportedly being used for recreational purposes. As ketamine use can result in urinary dysfunction, we conducted the present study to investigate how methoxetamine affects the bladder. A cystometry investigation showed that female Sprague-Dawley rats experienced increased micturition frequency bladder dysfunction after receiving a daily intraperitoneal injection of 30 mg/kg methoxetamine or ketamine for periods of 4 or 12 weeks. Histologic examinations of rat bladder tissue revealed damaged urothelium barriers, as well as evidence of inflammatory cell infiltration and matrix deposition. The drug-treated rats showed significantly upregulated levels of pro-inflammatory cytokines such as IL-1β, IL-6, CCL-2, CXCL-1, CXCL-10, NGF, and COX-2. In addition, interstitial fibrosis was confirmed by increased levels of collagen I, collagen III, fibronectin and TGF-β. Besides direct toxic effect on human urothelial cells, methoxetaminealso induced the upregulation related cytokines. Our results indicate that long term methoxetamine treatment can induce bladder dysfunction and inflammation in rats. Methoxetamine was confirmed to produce direct toxic and pro-inflammatory effects on human urothelial cells. Methoxetamine-associated bladder impairment may be similar to ketamine-induced cystitis.

Highlights

Methoxetamine (MXE) is a structural analog of ketamine (KET), which serves as a N-methyl-Daspartate receptor antagonist [1]
Various researchers have used cystometry to objectively evaluate the status of the lower urinary tract in animal models of ketamine-induced cystitis [11,16,17], and the results found in our KET-treated rats were consistent with the findings in those previous studies
These results suggest that the cytokines may not have been released as a result of chronic inflammation, and due to the biological effect of MXE on urothelial cells

Summary

Introduction

Methoxetamine (MXE) is a structural analog of ketamine (KET), which serves as a N-methyl-Daspartate receptor antagonist [1]. MXE binds to serotonin transporter to suppress the re-uptake of 5-hydroxytryptamine and ensure proper levels of 5-hydroxytryptamine in the brain. MXE has been shown to increase dopamine secretion and suppress dopamine re-uptake [2]. MXE has only recently been studied as a novel synthetic psychoactive drug, and in 2010, was reported to produce a variety of effects in humans, including feelings of euphoria, calmness, intensive sensations, and physical dissociation, as well as hallucinations and near-death experiences. In 2011, MXE attracted attention for its reported recreational use [3]. Only a limited amount of MXE-related pharmacologic and toxicology data are available and additional studies of its properties and effects are needed.

Methods

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Discussion

Conclusion