2025-03-182025-03-182024-04-10Suarez Pereira, I., Lopez Martin, C., Camarena Delgado, C., Llorca Torralba, M., Gonzalez Saiz, F., Ruiz Laza, R.,...,Berrocoso, E. (2024). Nerve injury triggers time-dependent activation of the locus coeruleus, influencing spontaneous pain-like behavior in rats.. Anesthesiology, 141 (1), 131-150. https://doi.org/10.1097/ALN.0000000000005006.0003-30221528-1175https://hdl.handle.net/11441/170495Pain Medicine A nesthesiology, V 141 • NO 1 July 2024 131 ediTOR’S PeRSPecTiVe What We Already Know about This Topic • Increasing evidence suggests the involvement of the noradrenergic locus coeruleus in the dynamic modulation of nociception • The role of neuronal projections from the locus coeruleus to the spi- nal cord and to the rostral anterior cingular cortex in the modulation of neuropathic pain over time is incompletely understood What This Article Tells us That Is New • In an experimental model of chronic constriction nerve injury in rats, a combination of genetic and histologic approaches revealed a biphasic time-dependent role for locus coeruleus neurons in mod- ulating nociceptive responses • After 2 days of nerve injury, activation of locus coeruleus neurons projecting to spinal cord played a role in attenuating pain-like behavior while activation of locus coeruleus neurons projecting to the rostral anterior cingular cortex amplified nociceptive responses • After 30 days of nerve injury, only the projections from locus coe- ruleus neurons to the rostral anterior cingular cortex contributed to the modulation of pain-like behavior in this experimental model The locus coeruleus (LC) noradrenergic system is the main source of noradrenaline in the central nervous system, and it is a key brain area involved in pain plas- ticity.1–3 Numerous studies indicate that the LC is engaged by acute noxious stimuli or inflammation, promoting feed- back inhibition of pain.4–6 However, recent studies suggest that the LC does not fulfill a uniform role in chronic pain, but rather, it changes dynamically through the activation of specific LC projections while others are silenced as pain Nerve Injury Triggers Time-dependent Activation of the Locus Coeruleus, Influencing Spontaneous Pain-like Behavior in Rats Irene Suárez-Pereira, Ph.D., Carolina López-Martín, M.Sc., Carmen Camarena-Delgado, Ph.D., Meritxell Llorca-Torralba, Ph.D., Francisco González-Saiz, M.D., Rocío Ruiz, Ph.D., Martiniano Santiago, Ph.D., Esther Berrocoso, Ph.D. A nesthesiology 2024; 141:131–50 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, the authors explored the cellular cFos activ- ity 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 after noxious mechanical stimulation. LC activity was evaluated through chemogenetic and pharmacologic 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 pro- jection 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 mod- ified by stimulation. No cFos expression was found in the CCI-LT LC ipsilateral (ipsi)/contralateral (contra)→SC. Chemogenetics showed that CCI-ST is associated with greater spontaneous pain-like behavior when the LC ipsi is blocked, or by selec- tively blocking the LC ipsi→SC projection. Activation of the LC ipsi or LC ipsi/contra→ SC dampened pain-like behavior. Moreover, Designer Receptor Exclusively Activated by Designer Drugs (DREADDs)–mediated inactivation of the CCI-ST LC ipsi→rACC or CCI-LT LC ipsi/contra→rACC pathway, or intra-rACC antagonism of α-adrenoreceptors, also dampens pain-like behavior. conclusions: In the short term, activation of the LC after CCI attenuates spontaneous pain-like behaviors via projections to the SC while increasing nociception via projections to the rACC. In the long term, only the projec- tions from the LC to the rACC contribute to modulate pain-like behaviors in this model.application/pdf19engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccess10.1097/ALN.0000000000005006