Divergent Modulation of Nociception by Glutamatergic and GABAergic Neuronal Subpopulations in the Periaqueductal Gray

Abstract

The ventrolateral periaqueductal gray (vlPAG) constitutes a major descending pain modulatory system and is a crucial site for opioid-induced analgesia. A number of previous studies have demonstrated that glutamate and GABA play critical opposing roles in nociceptive processing in the vlPAG. It has been suggested that glutamatergic neurotransmission exerts antinociceptive effects, whereas GABAergic neurotransmission exert pronociceptive effects on pain transmission, through descending pathways. The inability to exclusively manipulate subpopulations of neurons in the PAG has prevented direct testing of this hypothesis. Here, we demonstrate the different contributions of genetically defined glutamatergic and GABAergic vlPAG neurons in nociceptive processing by employing cell type-specific chemogenetic approaches in mice. Global chemogenetic manipulation of vlPAG neuronal activity suggests that vlPAG neural circuits exert tonic suppression of nociception, consistent with previous pharmacological and electrophysiological studies. However, selective modulation of GABAergic or glutamatergic neurons demonstrates an inverse regulation of nociceptive behaviors by these cell populations. Selective chemogenetic activation of glutamatergic neurons, or inhibition of GABAergic neurons, in vlPAG suppresses nociception. In contrast, inhibition of glutamatergic neurons, or activation of GABAergic neurons, in vlPAG facilitates nociception. Our findings provide direct experimental support for a model in which excitatory and inhibitory neurons in the PAG bidirectionally modulate nociception.

Cell type-specific modulation of sensory and affective components of itch in the periaqueductal gray

“…It is unclear how distinct neuronal populations integrate and modulate different sensations. We and others have shown that the vlPAG GABAergic and glutamatergic neurons differentially modulate pain neurotransmission 29,30,[35][36][37][46][47][48][49][50] . Itch and pain exhibit a reciprocal relationship at the behavioral level.…”

“…It is important to note that we recently demonstrated that CNO reliably modulates the activity of vlPAG glutamatergic neurons expressing DREADDs 36 . Three weeks after DREADD injection, robust viral expression was observed in the vlPAG (Figure 5a).…”

“…The results above show that excitation of vlPAG neurons leads to suppression of chloroquine-evoked scratching, whereas inhibition of vlPAG neuronal activity potentiates chloroquine-evoked scratching. However, the vlPAG is composed of both inhibitory GABAergic and excitatory glutamatergic neurons, which are non-overlapping populations [35][36][37] . The chemogenetic manipulations of vlPAG neuronal activity in the prior experiments do not distinguish between these two populations.…”

Glutamatergic cells in the periaqueductal gray matter mediate sensory inputs after bladder stimulation in freely moving rats

“…The main inhibitory GABAergic input to the vlPAG relevant to micturition is projected from the dlPAG . Glutamatergic cells of the vlPAG also control other important functions, including freezing behavior and analgesia . These two functions are controlled by two separate cell groups in the vlPAG .…”

“…20 Glutamatergic cells of the vlPAG also control other important functions, including freezing behavior and analgesia. 21 These two functions are controlled by two separate cell groups in the vlPAG. 19 Whether these cell groups are separate from those vlPAG glutamatergic cells controlling the voiding, or have some overlap remains to be elucidated.…”