Repeat mild traumatic brain injuries (RmTBI) modify nociception and disrupt orexinergic connectivity within the descending pain pathway

The Journal of Headache and Pain

Research

Naomi MacPherson¹  Richelle Mychasiuk¹  Jennaya Christensen¹  Crystal Li¹  Glenn R. Yamakawa¹ 

[1] Department of Neuroscience, Central Clinical School, 99 Commercial Road, 3004, Melbourne, VIC, Australia;

关键词: Concussion;    CGRP;    Lateral hypothalamus;    Lateral parabrachial nucleus;    Periaqueductal grey;    Post-traumatic headache;   

DOI  :  10.1186/s10194-023-01608-y

 received in 2023-03-06, accepted in 2023-06-07,  发布年份 2023

来源: Springer

【 摘 要 】

Repeat mild traumatic brain injuries (RmTBI) result in substantial burden to the public health system given their association with chronic post-injury pathologies, such as chronic pain and post-traumatic headache. Although this may relate to dysfunctional descending pain modulation (DPM), it is uncertain what mechanisms drive changes within this pathway. One possibility is altered orexinergic system functioning, as orexin is a potent anti-nociceptive neuromodulator. Orexin is exclusively produced by the lateral hypothalamus (LH) and receives excitatory innervation from the lateral parabrachial nucleus (lPBN). Therefore, we used neuronal tract-tracing to investigate the relationship between RmTBI and connectivity between lPBN and the LH, as well as orexinergic projections to a key site within the DPM, the periaqueductal gray (PAG). Prior to injury induction, retrograde and anterograde tract-tracing surgery was performed on 70 young-adult male Sprague Dawley rats, targeting the lPBN and PAG. Rodents were then randomly assigned to receive RmTBIs or sham injuries before undergoing testing for anxiety-like behaviour and nociceptive sensitivity. Immunohistochemical analysis identified distinct and co-localized orexin and tract-tracing cell bodies and projections within the LH. The RmTBI group exhibited altered nociception and reduced anxiety as well as a loss of orexin cell bodies and a reduction of hypothalamic projections to the ventrolateral nucleus of the PAG. However, there was no significant effect of injury on neuronal connectivity between the lPBN and orexinergic cell bodies within the LH. Our identification of structural losses and the resulting physiological changes in the orexinergic system following RmTBI begins to clarify acute post-injury mechanistic changes that drive may drive the development of post-traumatic headache and the chronification of pain.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

Fig. 1

40854_2023_491_Article_IEq17.gif

Fig. 2