(328) Divergent PAG neuronal populations drive nociceptive and pruritus processing

Abstract

Chronic itch, like chronic pain, is a major clinical problem. Despite the similarities between itch and pain, the underlying neural circuitry for itch is poorly understood, as is the mechanism by which itch is suppressed by pain. Profound analgesia occurs with stimulation of the periaqueductal gray, however the precise role of the PAG in itch is unknown. We hypothesized that specific subsets of neurons within the PAG could suppress itch and provide a neural substrate for the inverse interaction between itch and pain. To determine the role of PAG in mediating itch and pain, we activated or inhibited PAG neurons using engineered G-protein coupled receptors (GPCRs) activated exclusively by synthetic, systemically administered small molecules (i.e., DREADD technology). Engineered excitatory (Gq) or inhibitory (Gi) GPCRs were expressed in PAG neurons via adeno-associated viral vectors. We found that chemogenetic activation of non-specific PAG neurons produced a reduction of both itch and pain, whereas inhibition of non-specific PAG neurons resulted in enhanced itch and pain. In contrast, when only the GABAergic neurons in the PAG were targeted using VGAT Cre mice, activation resulted in decreased itch, but increased behaviors. Conversely, inhibition of PAG GABAergic neurons resulted in increased itch, but decreased pain behaviors. When glutamatergic neurons in the PAG were selectively targeted we found that activation led to enhanced itch and decreased pain, while inhibition neurons produced decreased itch and increased pain. We conclude that the PAG bidirectionally modulates itch and pain signaling and is a neural control center for pruritus.