Long-term depression (LTD) of somatosensory processing was demonstrated in spinal slice preparations. Although LTD could be reliably induced in vitro, inconsistent results were encountered under in vivo conditions. LTD of sensorimotor processing was addressed in 74 Balb/c mice under general barbiturate anaesthesia. Changes in brainstem sensorimotor processing were measured by the jaw-opening reflex (JOR). The JOR was elicited by electrical test stimulation (0.1 Hz) of the tongue musculature and recorded in the digastric muscle. Conditioning electrical low-frequency stimulation (LFS; 1 Hz) and high-frequency stimulation (HFS; 100 Hz) were applied via the same tongue electrodes. Test and conditioning stimulations were performed with two stimulus intensities of 1.5 and 4 times the JOR threshold. Low and high intensity LFS induced a sustained decrease of JOR integral by 43% and 53%, respectively, for more than one hour. After additional HFS the JOR partly recovered from LTD. Sole HFS induced a transient JOR increase for less than 10 min. Preceding systemic administration of the dopamine D2-like receptor agonist quinpirole, attenuated the effect of LFS (14%), whereas preceding administration of the D2-like receptor antagonist sulpiride increased the effect of LFS on the JOR (64%). The LTD of the JOR in mice may be an appropriate model to investigate central mechanisms and pharmacology of synaptic plasticity. This approach in mice provides the opportunity to address genetically manipulated mice models.