Activation of Extracellular Signal-Regulated Kinases (ERK 1/2) in the Locus Coeruleus Contributes to Pain-Related Anxiety in Arthritic Male Rats

Background: There is increasing evidence suggesting that the Locus Coeruleus plays a role in pain-related anxiety. Indeed, we previously found that prolonged arthritis produces anxiety-like behavior in rats, along with enhanced expression of phosphorylated extracellular signal-regulated kinase 1/2 (a marker of plasticity) in the Locus Coeruleus. However, it is unknown how this effect correlates with the electrophysiological activity of Locus Coeruleus neurons or pain-related anxiety. Methods: Using the complete Freund's adjuvant model of monoarthritis in male Sprague-Dawley rats, we studied the behavioral attributes of pain and anxiety as well as Locus Coeruleus electrophysiology in vivo 1 (MA1W) and 4 weeks (MA4W) after disease induction. Results: The manifestation of anxiety in MA4W was accompanied by dampened tonic Locus Coeruleus activity, which was coupled to an exacerbated evoked Locus Coeruleus response to noxious stimulation of the inflamed and healthy paw. When a mitogen-activating extracellular kinase inhibitor was administered to the contralateral Locus Coeruleus of MA4W, the phosphorylated extracellular signal-regulated kinase 1/2 levels in the Locus Coeruleus were restored and the exaggerated evoked response was blocked, reversing the anxiogenic-like behavior while pain hypersensitivity remained unaltered. Conclusion: As phosphorylated extracellular signal-regulated kinase 1/2 blockade in the Locus Coeruleus relieved anxiety and counteracted altered LC function, we propose that phosphorylated extracellular signal-regulated kinase 1/2 activation in the Locus Coeruleus plays a crucial role in pain-related anxiety.This work was supported by the "Catedra Externa del Dolor Fundacion Grunenthal/Universidad de Cadiz," which paid a grant to the first author; the "Catedra em Medicina da Dor from Fundacao Grunenthal-Portugal and Faculdade de Medicina da Universidade do Porto"; co-financed by the Fondo Europeo de Desarrollo Regional "Una manera de hacer Europa" (PI13/02659); the "Ministerio de Economia y Competitividad", co-financed byFEDER (SAF2015-68647-R (MINECO/FEDER)); CIBERSAM G18; the "Consejeria de Economia, Innovacion, Ciencia y Empleo de la Junta de Andalucia", Seville, Spain (CTS-510 and Proyecto de Excelencia: CTS-7748); 2015 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation; Fundacion Espanola de Dolor (travel fellowship granted to Gisela Borges - 1536); and Gobierno Vasco (IT747-13)