Background & Aims

The Rostral ventromedial medulla (RVM) is known to control pain sensitivity in a bidirectional manner, and this is thought to be through engagement of descending pathways that project to the spinal dorsal horn. Within the RVM, pro and antinociceptive neurons have been identified based on their responses to nociceptive stimuli. The functional diversity of these pathways, how they control pain sensitivity and under which physiological conditions they are engaged are not fully understood. To address these open questions, we aimed to identify populations of descending RVM neurons that are relevant to pain perception and determine how they influence the nociceptive system. Because inhibition at the level of the spinal cord is critical for normal pain sensitivity, we decided to focus on the inhibitory projection neurons descending from the RVM to the spinal cord.

Methods

Surgical procedures: spinal cord and hindbrain injections
Multiplex in situ hybridisation, performed according to manufacturer’s specifications (ACD bio)
Perfusion fixation (4% paraformaldehyde) and Immunostaining
Confocal microscopy
Behavioural assays: Hargreaves plantar assay, cold plantar assay, von Frey, brush test, hot plate.

Results

We identify several distinct types of descending projection neuron in the ventral hindbrain, including inhibitory neurons. Within the inhibitory neurons, we can identify groups that are distinct in terms of their neurotransmitter content, anatomical location in the hindbrain, and projection targets in the spinal cord. These groups can be accessed genetically using intersectional targeting strategies, AAV-mediated gene transfer, and retrograde transduction via their axon terminals in the spinal cord.

Using these genetic strategies, we were able to functionally manipulate these different projection neuron types, revealing distinct roles in processing of somatosensory information in awake behaving animals. We find that a subset of inhibitory projection neurons is required for normal mechanical sensitivity, but their activation has little effect on baseline sensitivity. In contrast selective activation of a separate population can strongly reduce cutaneous sensitivity.

Conclusions

Descending inhibitory RVM projection neurons are heterogeneous and are comprised of different functional groups. These have distinct features and play diverse functional roles in controlling pain sensitivity. This aids our understanding of how endogenous pain control systems work and reveal neuronal components that could be targeted for pain treatment.

References

1. Trends Neurosci (2023) Jul;46(7):539-550. doi: 10.1016/j.tins.2023.04.002. Epub 2023 May 9.
Cell type-specific dissection of sensory pathways involved in descending modulation
Eileen Nguyen, Jose G Grajales-Reyes, Robert W Gereau 4th, Sarah E Ross

2. Front Pain Res (Lausanne) (2022) Jun 28:3:932476. doi: 10.3389/fpain.2022.932476. eCollection 2022.
Shifting the Balance: How Top-Down and Bottom-Up Input Modulate Pain via the Rostral Ventromedial Medulla
Qiliang Chen, Mary M Heinricher

Presenting Author

Robert Ganley

Poster Authors

Robert P. Ganley, PhD

PhD

National Institutes of Health (NIH)

Lead Author

E-mail

Topics

  • Models: Chronic Pain - Neuropathic