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Papers of the Week

Papers: 2 Dec 2023 - 8 Dec 2023

2023 Nov 22

J Neurosci


Low-frequency stimulation of Trpv1-lineage peripheral afferents potentiates the excitability of spino-periaqueductal gray projection neurons.


Brewer CL, Kauer JA


High-threshold dorsal root ganglion (HT DRG) neurons fire at low frequencies during inflammatory injury, and low-frequency stimulation (LFS) of HT DRG neurons selectively potentiates excitatory synapses onto spinal neurons projecting to periaqueductal gray (spino-PAG). Here, in male and female mice, we have identified an underlying peripheral sensory population driving this plasticity and its effects on the output of spino-PAG neurons. We provide the first evidence that Trpv1-lineage sensory neurons predominantly induce burst firing, a unique mode of neuronal activity, in lamina I spino-PAG projection neurons. We modeled inflammatory injury by optogenetically stimulating Trpv1+ primary afferents at 2 Hz for 2 min (LFS), as peripheral inflammation induces 1-2 Hz firing in high-threshold C fibers. LFS of Trpv1+ afferents enhanced the synaptically evoked and intrinsic excitability of spino-PAG projection neurons, eliciting a stable increase in the number of action potentials (APs) within a Trpv1+ fiber-induced burst, while decreasing the intrinsic AP threshold and increasing the membrane resistance. Further experiments revealed that this plasticity required Trpv1+ afferent input, postsynaptic G protein-coupled signaling, and NMDA receptor activation. Intriguingly, an inflammatory injury and heat exposure also increased APs per burst, These results suggest that inflammatory injury-mediated plasticity is driven though Trpv1+ DRG neurons and amplifies the spino-PAG pathway. Spinal inputs to the PAG could play an integral role in its modulation of heat sensation during peripheral inflammation, warranting further exploration of the organization and function of these neural pathways. Peripheral injury can lead to long-term modifications in spinal cord circuits and nociceptive processing. Electrical stimulation that models nerve activity during inflammatory injury selectively potentiates dorsal root ganglion (DRG) excitatory C fiber synapses onto spino-periaqueductal gray (spino-PAG) projection neurons. However, it is unknown if this potentiation 1) is driven by specific DRG subtypes and 2) alters the supraspinal output of this pathway. Here we demonstrate that Trpv1-lineage DRG neurons can persistently enhance both the synaptically driven and intrinsic excitability of spino-PAG projection neurons. We examine the mechanistic underpinnings of this enhanced excitability and provide evidence that this plasticity is evoked specifically during inflammatory injury and heat exposure and could influence inflammation-induced heat sensitization and pain perception.