A critical brainstem relay for mediation of diffuse noxious inhibitory controls

Author:

Kucharczyk Mateusz W12ORCID,Di Domenico Francesca1,Bannister Kirsty1ORCID

Affiliation:

1. Central Modulation of Pain, Institute of Psychiatry, Psychology and Neuroscience, King’s College London , London SE1 1UL , UK

2. Laboratory of Neurophysiology, Department of Biochemical Toxicology, Chair of Toxicology, Faculty of Pharmacy, Jagiellonian University Medical College , Krakow 30-688 , Poland

Abstract

Abstract The CNS houses naturally occurring pathways that project from the brain to modulate spinal neuronal activity. The noradrenergic locus coeruleus (the A6 nucleus) originates such a descending control whose influence on pain modulation encompasses an interaction with a spinally projecting non-cerulean noradrenergic cell group. Hypothesizing the origin of an endogenous pain inhibitory pathway, our aim was to identify this cell group. A5 and A7 noradrenergic nuclei also spinally project. We probed their activity using an array of optogenetic manipulation techniques during in vivo electrophysiological experimentation. Interestingly, noxious stimulus evoked spinal neuronal firing was decreased upon opto-activation of A5 neurons (two-way ANOVA with Tukey post hoc, P < 0.0001). Hypothesizing that this may reflect activity in the noradrenergic diffuse noxious inhibitory control circuit, itself activated upon application of a conditioning stimulus, we opto-inhibited A5 neurons with concurrent conditioning stimulus application. Surprisingly, no spinal neuronal inhibition was observed; activity in the diffuse noxious inhibitory control circuit was abolished (two-way ANOVA, P < 0.0001). We propose that the A5 nucleus is a critical relay nucleus for mediation of diffuse noxious inhibitory controls. Given the plasticity of diffuse noxious inhibitory controls in disease, and its back and forward clinical translation, our data reveal a potential therapeutic target.

Funder

Academy of Medical Sciences

Medical Research Council

National Centre for the Replacement, Refinement and Reduction of Animals in Research

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

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