Descending GABAergic Neurons of the RVM That Mediate Widespread Bilateral Antinociception

Abstract

Neurons projecting from the rostral ventromedial medulla (RVM) to the spinal dorsal horn are critical elements of endogenous pain control systems. Here, we describe a GABA/glycinergic pathway that predominantly innervates the superficial dorsal horn. Anatomical and optogenetic tracing of these neurons from a single unilateral site of the lumbar spinal cord indicated that these neurons give rise to a dense bilateral innervation of the spinal cord along its entire rostrocaudal axis. Chemogenetic activation of these neurons caused a bilateral and widespread reduction in heat, cold, and mechanical sensitivity, while their silencing with tetanus toxin induced allodynia and spontaneous pain-like aversive behaviors. Consistent with a continuous role in the prevention of spontaneous pain, many descending RVM GABAergic neurons were found to be tonically active. This pathway may therefore be relevant for widespread conditioned analgesia, while its dysfunction may underlie chronic widespread pain syndromes.

Inputs to the locus coeruleus from the periaqueductal gray and rostroventral medulla shape opioid-mediated descending pain modulation

“…S7). This may be due to interactions between pro-and antinociceptive RVM projections to the spinal cord (2,98). LC-projecting RVM neurons do not appear to project to the spinal cord and instead send ascending projections to the thalamus, making it currently unclear how LC-projecting RVM neurons might fit into the canonical On-and Off-cell framework.…”

Inputs to the locus coeruleus from the periaqueductal gray and rostroventral medulla shape opioid-mediated descending pain modulation

“…While chemogenetic inhibition of these RVM outputs specifically to LC caused spinal NA-dependent antinociception, presumably via disinhibition of LC, inhibiting all RVM inhibitory neurons had no effect on either opioid-naïve nociception or morphine antinociception ( Figure S5 ). This may be due to interactions between pro– and antinociceptive RVM projections to the spinal cord ( 2 , 35 ). Interestingly, LC-projecting RVM neurons do not appear to project to the spinal cord and instead send ascending projections to the thalamus.…”