Targeted anatomical and functional identification of antinociceptive and pronociceptive serotonergic neurons that project to the spinal dorsal horn

Abstract

Spinally-projecting serotonergic neurons play a key role in controlling pain sensitivity and can either increase or decrease nociception depending on physiological context. It is currently unknown how serotonergic neurons mediate these opposing effects. Utilizing virus-based strategies and Tph2-Cre transgenic mice, we identified two anatomically separated populations of serotonergic hindbrain neurons located in the lateral paragigantocellularis (LPGi) and the medial hindbrain, which respectively innervate the superficial and deep spinal dorsal horn and have contrasting effects on sensory perception. Our tracing experiments revealed that serotonergic neurons of the LPGi were much more susceptible to transduction with spinally injected AAV2retro vectors than medial hindbrain serotonergic neurons. Taking advantage of this difference, we employed intersectional chemogenetic approaches to demonstrate that activation of the LPGi serotonergic projections decreases thermal sensitivity, whereas activation of medial serotonergic neurons increases sensitivity to mechanical von Frey stimulation. Together these results suggest that there are functionally distinct classes of serotonergic hindbrain neurons that differ in their anatomical location in the hindbrain, their postsynaptic targets in the spinal cord, and their impact on nociceptive sensitivity. The LPGi neurons that give rise to rather global and bilateral projections throughout the rostrocaudal extent of the spinal cord appear to be ideally posed to contribute to widespread systemic pain control.

Effects of stress contagion on anxiogenic‐ and orofacial inflammatory pain‐like behaviors with brain activation in mice

“…Further, it is possible that the modulatory effects of stress contagion and social defeat stress on the 5-HT mechanism in the LPGi could be different from those in the nucleus raphe magnus. Evidence could support our speculations that 5-HT neurons in the LPGi and nucleus raphe magnus are shown to have distinct roles in the regulation of nociceptive processing and cardiovascular functions [53][54][55].…”

Descending GABAergic Neurons of the RVM That Mediate Widespread Bilateral Antinociception

“…However, these studies may not include all projections due to the known tropism of AAV2retro vectors 12,32 . We decided to study the inhibitory population, although there are almost certainly other functionally important groups of projection neurons in this area, many of which were not captured in our sample, such as the serotonergic neurons of the raphe magnus 13,33,34 .…”

Understanding of Spinal Wide Dynamic Range Neurons and Their Modulation on Pathological Pain

“…117 However, the antinociceptive and pronociceptive effects of the descending serotonergic pathway in pain modulation remain controversial. 118 According to multiple studies, there are notable variances in the effects of various subtypes of 5-HT receptors on the A-components, C-components, and postdischarges of WDR neurons. [119][120][121] The heterogeneous effects of the serotonergic descending pathway on nociception, as observed in WDR neurons, may be attributed to the activation of different receptor subtypes on the neuronal surface.…”