Nerve injury triggers time-dependent activation of the locus coeruleus, influencing spontaneous pain-like behavior in rats

Irene Suárez-Pereira; Carolina López-Martín; Carmen Camarena-Delgado; Meritxell Llorca-Torralba; Francisco González-Saiz; Rocío Ruiz; Martiniano Santiago; Esther Berrocoso

doi:10.1097/ALN.0000000000005006

Nerve injury triggers time-dependent activation of the locus coeruleus, influencing spontaneous pain-like behavior in rats

Anesthesiology. 2024 Apr 10. doi: 10.1097/ALN.0000000000005006. Online ahead of print.

Authors

Irene Suárez-Pereira^{1

2

3}, Carolina López-Martín^{1

2

3}, Carmen Camarena-Delgado^{3

4

5}, Meritxell Llorca-Torralba^{1

3

6}, Francisco González-Saiz^{1

7

8}, Rocío Ruiz⁹, Martiniano Santiago⁹, Esther Berrocoso^{1

2

3}

Affiliations

¹ Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
² Neuropsychopharmacology and Psychobiology Research Group, Department of Neuroscience, Faculty of Medicine, University of Cádiz, Cádiz, Spain.
³ Instituto de Investigación e Innovación Biomédica de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain.
⁴ IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Milan, Italy.
⁵ Institute of Neuroscience (IN-CNR), National Research Council of Italy, Milan, Italy.
⁶ Neuropsychopharmacology and Psychobiology Research Group, Department of Cell Biology and Histology, University of Cádiz, Cádiz, Spain.
⁷ Department of Neuroscience, Faculty of Medicine, University of Cádiz, Cádiz, Spain.
⁸ Community Mental Health Unit of Villamartin, Hospital Universitario de Jerez, Cádiz, Spain.
⁹ Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Instituto de Biomedicina de Sevilla-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.

PMID: 38602502
DOI: 10.1097/ALN.0000000000005006

Abstract

Background: Dynamic changes in neuronal activity and in noradrenergic locus coeruleus (LC) projections have been proposed during the transition from acute to chronic pain. Thus, we explored the cellular cFos activity of the LC and its projections, in conjunction with spontaneous pain-like behavior in neuropathic rats.

Methods: Tyrosine hydroxylase:Cre and wild-type Long-Evans rats, males and females, were subjected to chronic constriction injury (CCI) for 2 (short-term, CCI-ST) or 30 days (long-term, CCI-LT), evaluating cFos and Fluoro-Gold expression in the LC, and its projections to the spinal cord (SC) and rostral anterior cingulate cortex (rACC). These tests were carried out under basal conditions (unstimulated) and following noxious mechanical stimulation. LC activity was evaluated through chemogenetic and pharmacological approaches, as were its projections, in association with spontaneous pain-like behaviors.

Results: CCI-ST enhanced basal cFos expression in the LC and in its projection to the SC, which increased further after noxious stimulation. Similar basal activation was found in the neurons projecting to the rACC, although this was not modified by stimulation. Strong basal cFos expression was found in CCI-LT, specifically in the projection to the rACC, which was again not modified by stimulation. No cFos expression was found in the CCI-LT LCipsi/contra→SC. Chemogenetics showed that CCI-ST is associated with greater spontaneous pain-like behavior when the LCipsi is blocked, or by selectively blocking the LCipsi→SC projection. Activation of the LCipsi or LCipsi/contra→SC dampened pain-like behavior. Moreover, DREADDs-mediated inactivation of the CCI-ST LCipsi→rACC or CCI-LT LCipsi/contra→rACC pathway, or intra-rACC antagonism of alpha-adrenoreceptors, also dampens pain-like behavior.

Conclusions: In the short term, activation of the LC following CCI attenuates spontaneous pain-like behaviors via projections to the SC while increases nociception via projections to the rACC. In the long term, only the projections from the LC to the rACC contribute to modulate pain-like behaviors in this model.