The posterior nucleus of thalamus (PO) is a higher-order nucleus involved in sensorimotor processing, including nociception. An important characteristic of PO is its wide range of activity profiles that vary across states of arousal, thought to underlie differences in somatosensory perception subject to attention and degree of consciousness. Furthermore, PO loses the ability to downregulate its activity level in some forms of chronic pain, suggesting that regulatory mechanisms underlying the normal modulation of PO activity may be pathologically altered. However, the mechanisms responsible for regulating such a wide dynamic range of activity are unknown. Here, we test a series of hypotheses regarding the function of several presynaptic receptors on both GABAergic and glutamatergic afferents targeting PO in mouse, using acute slice electrophysiology. We found that presynaptic GABABreceptors are present on both GABAergic and glutamatergic terminals in PO, but only those on GABAergic terminals are tonically active. We also found that release from GABAergic terminals, but not glutamatergic terminals, is suppressed by cholinergic activation and that a subpopulation of GABAergic terminals is regulated by cannabinoids. Finally, we discovered the presence of tonic currents mediated by extrasynaptic GABAAreceptors in PO that are heterogeneously distributed across the nucleus. Thus we demonstrate that multiple regulatory mechanisms concurrently exist in PO, and we propose that regulation of inhibition, rather than excitation, is the more consequential mechanism by which PO activity can be regulated.NEW & NOTEWORTHY The posterior nucleus of thalamus (PO) is a key sensorimotor structure, whose activity is tightly regulated by inhibition from several nuclei. Maladaptive plasticity in this inhibition leads to severe pathologies, including chronic pain. We reveal here, for the first time in PO, multiple regulatory mechanisms that modulate synaptic transmission within PO. These findings may lead to targeted therapies for chronic pain and other disorders.