Noradrenergic modulation of masseter muscle activity during natural rapid eye movement sleep requires glutamatergic signalling at the trigeminal motor nucleus

Abstract

Key pointsr A principal role of noradrenaline is to potentiate motoneuron output in response to excitatory transmitter input.r It is unknown if α-1 noradrenoceptor activation is sufficient to independently trigger masseter muscle activity during natural waking and sleeping behaviour in the absence of excitatory (glutamatergic) input.r Here, we use behavioural, neuropharmacological and electrophysiological techniques during rapid eye movement (REM) sleep to demonstrate that the excitatory effects of noradrenaline on motor output are lost in the absence of an endogenous glutamatergic drive.r These findings may shed light on the unremarkable therapeutic outcomes of aminergic drugs in treating certain sleep motor disorders, particularly during REM sleep.Abstract Noradrenergic neurotransmission in the brainstem is closely coupled to changes in muscle activity across the sleep-wake cycle, and noradrenaline is considered to be a key excitatory neuromodulator that reinforces the arousal-related stimulus on motoneurons to drive movement. However, it is unknown if α-1 noradrenoceptor activation increases motoneuron responsiveness to excitatory glutamate (AMPA) receptor-mediated inputs during natural behaviour. We studied the effects of noradrenaline on AMPA receptor-mediated motor activity at the motoneuron level in freely behaving rats, particularly during rapid eye movement (REM) sleep, a period during which both AMPA receptor-triggered muscle twitches and periods of muscle quiescence in which AMPA drive is silent are exhibited. Male rats were subjected to electromyography and electroencephalography recording to monitor sleep and waking behaviour. The implantation of a cannula into the trigeminal motor nucleus of the brainstem allowed us to perfuse noradrenergic and glutamatergic drugs by reverse microdialysis, and thus to use masseter muscle activity as an index of motoneuronal output. We found that endogenous excitation of both α-1 noradrenoceptor and AMPA receptors during waking are coupled to motor activity; however, REM sleep exhibits an absence of endogenous α-1 noradrenoceptor activity. Importantly, exogenous α-1 noradrenoceptor stimulation cannot reverse the muscle twitch suppression induced by AMPA receptor blockade and nor can it elevate muscle activity during quiet REM, a phase when endogenous AMPA receptor activity is subthreshold. We conclude that the presence of an endogenous glutamatergic drive is necessary for noradrenaline to trigger muscle activity at the level of the motoneuron in an animal behaving naturally.

A pilot study of nocturnal temporalis muscle activity in TMD diagnostic groups of women

“…23, 25 Alternatively, frequent low intensity muscle activity may be a sign of homeostatic dysregulation. This has been demonstrated recently by data from animal models showing that increased activity of the sympathetic nervous system resulted in increased trigeminal motor neuron excitability 26 and glial cell-mediated neuroplasticity of trigeminal ganglia primary afferents 27 and subnucleus caudalis interneurons, 28 and showing associations between stress, autonomic nervous system (ANS) dysregulation, and masticatory muscle activity. 29 In humans, increased masticatory muscle activities at low levels during sleep in subjects with self-reported anxiety and somatization compared to control subjects have been reported.…”

The anatomical, cellular and synaptic basis of motor atonia during rapid eye movement sleep

“…More recently Brooks and Peever revised their initial model to incorporate multiple receptors, including GABA A , GABA B , glycine, glutamate and noradrenaline, as being involved in the inhibition and disfacilitation of cranial orofacial motor neurons to trigger REM sleep muscle atonia (Brooks & Peever, ; Schwarz et al . ).…”

Night‐time autonomic nervous system ultradian cycling and masticatory muscle activity

“…In the light of the current results, the TMD diagnostic group differences reported for muscle activities associated with loads of ≤5 N may indicate that duration of low‐level masseter and temporalis muscle activities was influenced by relatively increased sympathetic or decreased parasympathetic spectral powers or both. Several recent publications have reported the influence of noradrenergic (sympathetic) and cholinergic (parasympathetic) activities on masticatory muscle use during sleep. The findings of concomitant cycling of low‐level masseter and temporalis EMG with ANS ultradian cycling support the premise that masticatory muscle activities reflect ANS function.…”

“…Several recent publications 11,18 The data from this pilot study should be considered preliminary, given the small sample. Also, the 18-year difference in mean ages between the sexes is a limitation because age is known to affect ANS activity.…”

“…It is known that the progression from sleep onset to deeper sleep stages reflects a shift towards greater activity of the parasympathetic component of the ANS, whereas, throughout the night, progression to lighter sleep states is associated with a shift towards greater activity of the sympathetic component . Furthermore, animal and human studies of ANS dysregulation demonstrate that night‐time masticatory muscle use may also reflect parasympathetic and sympathetic activities. Additionally, ANS dysregulation in the form of adrenergic (sympathetic) hyperactivity in rats produced glial cell inflammation and the commensurate hyper‐excitability of primary and secondary nociceptive neurons in the trigeminal ganglia and the spinal tract subnucleus caudalis .…”