Toll‐like receptor 4 mediates lipopolysaccharide‐induced emesis

BACKGROUND AND PURPOSE: Lipopolysaccharide (LPS) induces inflammation and sepsis through Toll-like receptor 4 (TLR4) activation. Common laboratory animals do not exhibit emesis, but administration of LPS in piglets, cats, and dogs induces emesis via peripheral mechanisms. However, no studies have confirmed whether TLR4 is involved or whether TLR4 antagonists have clinical utility as anti-emetics. EXPERIMENTAL APPROACH: Male Suncus murinus (house musk shrew) was implanted with radiotelemetry transmitters to examine whether LPS-induced emesis and physiological changes indicative of 'nausea' (PCIN) are mediated by TLR4. Because S. murinus is not a common laboratory species, we first characterised the distribution of TLR4 in the brain and periphery, and the potency of the TLR4 antagonist resatorvid on the isolated ileum. KEY RESULTS: TLR4 mRNA, first found in the brainstem and gastrointestinal tract, shared 68.94% homology with human TLR4. Resatorvid non-competitively antagonised the inhibitory action of LPS in the isolated ileum. Behavioural studies showed that LPS induced emesis dose-dependently, increased defaecation, reduced food intake, caused hyperthermia, and increased c-Fos and Iba1 expression in the brainstem. LPS increased the dominant frequency of gastric slow waves, with a shift towards an increase in the percent power of bradygastria. Resatorvid reduced emetic, defaecatory and hyperthermic responses, and the associated increases of c-Fos and Iba1 immunoreactivity. Resatorvid also antagonised the LPS-induced changes in food intake and effects on slow waves. CONCLUSIONS AND IMPLICATIONS: These studies demonstrate that TLR4 and, possibly, glial cell and neuronal activation are involved in the mechanisms of emesis and other behavioural changes induced by LPS.