Central inhibition of initiation of swallowing by systemic administration of diazepam and baclofen in anaesthetized rats

Abstract

Dysphagia is caused not only by neurological and/or structural damage but also by medication. We hypothesized memantine, dextromethorphan, diazepam, and baclofen, all commonly used drugs with central sites of action, may regulate swallowing function. Swallows were evoked by upper airway (UA)/pharyngeal distension, punctate mechanical stimulation using a von Frey filament, capsaicin or distilled water (DW) applied topically to the vocal folds, and electrical stimulation of a superior laryngeal nerve (SLN) in anesthetized rats and were documented by recording electromyographic activation of the suprahyoid and thyrohyoid muscles and by visualizing laryngeal elevation. The effects of intraperitoneal or topical administration of each drug on swallowing function were studied. Systemic administration of diazepam and baclofen, but not memantine or dextromethorphan, inhibited swallowing evoked by mechanical, chemical, and electrical stimulation. Both benzodiazepines and GABA receptor antagonists diminished the inhibitory effects of diazepam, whereas a GABA receptor antagonist diminished the effects of baclofen. Topically applied diazepam or baclofen had no effect on swallowing. These data indicate that diazepam and baclofen act centrally to inhibit swallowing in anesthetized rats. Systemic administration of diazepam and baclofen, but not memantine or dextromethorphan, inhibited swallowing evoked by mechanical, chemical, and electrical stimulation. Both benzodiazepines and GABA receptor antagonists diminished the inhibitory effects of diazepam, whereas a GABA receptor antagonist diminished the effects of baclofen. Topical applied diazepam or baclofen was without effect on swallowing. Diazepam and baclofen act centrally to inhibit swallowing in anesthetized rats.

Involvement of the epithelial sodium channel in initiation of mechanically evoked swallows in anaesthetized rats

“…each trial succeeded in evoking a swallow) using a series of von Frey filaments (Tsujimura et al . ). For the mouth, the soft palate (3 cm from the upper incisors) was stimulated.…”

“…With the rat in the supine position, a midline incision was made along the ventral aspect from the pogonion to the caudal portion of the neck. To monitor respiratory efforts, the trachea was cannulated at its caudal-most end with a luer stub adaptor, and a pressure transducer was attached to a side port of the tracheal cannula (Tsujimura et al 2017(Tsujimura et al , 2018. Bipolar enamel-coated copper wire electrodes (0.23 mm diameter and 2 mm interpolar distance) were inserted into the left suprahyoid (SH) and thyrohyoid (TH) muscles for electromyographic (EMG) recording.…”

“…The swallowing threshold was defined as the force (g) that evokes a swallow twice in two sequential trials (i.e. each trial succeeded in evoking a swallow) using a series of von Frey filaments (Tsujimura et al 2017). For the mouth, the soft palate (3 cm from the upper incisors) was stimulated.…”

“…Application of capsaicin to the pharyngolaryngeal region reliably evokes many swallows even in anaesthetized animals (Tsujimura et al . , ). Although TRPV1 is activated by heat and mechanical stimulation (Flynn et al .…”

“…For example, capsaicin, which activates transient receptor potential vanilloid 1 (TRPV1) expressed in C-fibres and small-diameter A-fibres, could be a therapeutic agent for dysphagia (Ebihara et al 2011). Application of capsaicin to the pharyngolaryngeal region reliably evokes many swallows even in anaesthetized animals (Tsujimura et al 2013(Tsujimura et al , 2017. Although TRPV1 is activated by heat and mechanical stimulation (Flynn et al 2014), a primary role of capsaicin-sensitive nerves in natural swallowing of a food bolus, liquid and saliva is very doubtful because the nerves are believed to be noxious C-and A-fibres (Valtschanoff et al 2001).…”