Citation

Llorca-Torralba M, Camarena-Delgado C, Suárez-Pereira I, Bravo L, Mariscal P, Garcia-Partida JA, López-Martín C, Wei H, Pertovaara A, Mico JA, Berrocoso E. Brain 2021; ePub(ePub): ePub.

Copyright

(Copyright © 2021, Oxford University Press)

DOI

10.1093/brain/awab239

PMID

unavailable

Abstract

There is strong comorbidity between chronic pain and depression, although the neural circuits and mechanisms underlying this association remain unclear. By combining immunohistochemistry, tracing studies and western-blotting, with the use of different DREADDs (Designer Receptor Exclusively Activated by Designer Drugs) and behavioural approaches in a rat model of neuropathic pain (chronic constriction injury), we explore how this comorbidity arises. To this end, we evaluated the time-dependent plasticity of noradrenergic-locus coeruleus (LC) neurons relative to the site of injury: ipsilateral (LCipsi) or contralateral (LCcontra) at three different time points: short- (2 days), mid- (7 days), and long-term (30-35 days from nerve injury). Nerve injury led to sensorial hypersensitivity from the onset of injury, whereas depressive-like behavior was only evident following long-term pain. Global chemogenetic blockade of the LCipsi system alone increased short-term pain sensitivity while the blockade of the LCipsi or LCcontra relieved pain-induced depression. The asymmetric contribution of LC-modules was also evident as neuropathy develops. Hence, chemogenetic blockade of the LCipsi→spinal cord projection, increased pain-related behaviours in the short-term. However, this lateralized circuit is not universal as the bilateral chemogenetic inactivation of the LC-rostral anterior cingulate cortex (rACC) pathway or the intra-rACC antagonism of alpha1- and alpha2-adrenoreceptors reversed long-term pain-induced depression. Furthermore, chemogenetic LC to spinal cord activation, mainly through LCipsi, reduced sensorial hypersensitivity irrespective of the time post-injury. Our results indicate that asymmetric activation of specific LC modules promotes early restorative-analgesia, as well as late depressive-like behavior in chronic pain and depression comorbidity.

Language: en

Keywords

depression; anterior cingulate cortex; locus coeruleus; neuropathic pain; spinal cord