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



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.



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.



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.
Neuropsychopharmacology and Psychobiology Research Group, Department of Neuroscience, University of Cádiz, Cádiz, Spain (Drs Borges and Mico); Departamento de Biomedicina-Unidade de Biologia Experimental, da Faculdade de Medicina da Universidade do Porto (FMUP), Porto, Portugal (Drs Borges and Neto); Instituto de Biologia Molecular e Celular (IBMC) e Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, Porto, Portugal (Drs Borges and Neto); Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU, Leioa, Spain (Drs Miguelez and Ugedo); Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain (Drs Mico and Berrocoso); Neuropsychopharmacology and Psychobiology Research Group, Department of Psychology, University of Cádiz, Cádiz, Spain (Dr Berrocoso); Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain (Drs Mico and Berrocoso).
Gisela
G
Borges
Neuropsychopharmacology and Psychobiology Research Group, Department of Neuroscience, University of Cádiz, Cádiz, Spain (Drs Borges and Mico); Departamento de Biomedicina-Unidade de Biologia Experimental, da Faculdade de Medicina da Universidade do Porto (FMUP), Porto, Portugal (Drs Borges and Neto); Instituto de Biologia Molecular e Celular (IBMC) e Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, Porto, Portugal (Drs Borges and Neto); Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU, Leioa, Spain (Drs Miguelez and Ugedo); Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain (Drs Mico and Berrocoso); Neuropsychopharmacology and Psychobiology Research Group, Department of Psychology, University of Cádiz, Cádiz, Spain (Dr Berrocoso); Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain (Drs Mico and Berrocoso).
Cristina
C
Miguelez
Neuropsychopharmacology and Psychobiology Research Group, Department of Neuroscience, University of Cádiz, Cádiz, Spain (Drs Borges and Mico); Departamento de Biomedicina-Unidade de Biologia Experimental, da Faculdade de Medicina da Universidade do Porto (FMUP), Porto, Portugal (Drs Borges and Neto); Instituto de Biologia Molecular e Celular (IBMC) e Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, Porto, Portugal (Drs Borges and Neto); Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU, Leioa, Spain (Drs Miguelez and Ugedo); Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain (Drs Mico and Berrocoso); Neuropsychopharmacology and Psychobiology Research Group, Department of Psychology, University of Cádiz, Cádiz, Spain (Dr Berrocoso); Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain (Drs Mico and Berrocoso).
Fani
F
Neto
Neuropsychopharmacology and Psychobiology Research Group, Department of Neuroscience, University of Cádiz, Cádiz, Spain (Drs Borges and Mico); Departamento de Biomedicina-Unidade de Biologia Experimental, da Faculdade de Medicina da Universidade do Porto (FMUP), Porto, Portugal (Drs Borges and Neto); Instituto de Biologia Molecular e Celular (IBMC) e Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, Porto, Portugal (Drs Borges and Neto); Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU, Leioa, Spain (Drs Miguelez and Ugedo); Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain (Drs Mico and Berrocoso); Neuropsychopharmacology and Psychobiology Research Group, Department of Psychology, University of Cádiz, Cádiz, Spain (Dr Berrocoso); Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain (Drs Mico and Berrocoso).
Juan Antonio
JA
Mico
Neuropsychopharmacology and Psychobiology Research Group, Department of Neuroscience, University of Cádiz, Cádiz, Spain (Drs Borges and Mico); Departamento de Biomedicina-Unidade de Biologia Experimental, da Faculdade de Medicina da Universidade do Porto (FMUP), Porto, Portugal (Drs Borges and Neto); Instituto de Biologia Molecular e Celular (IBMC) e Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, Porto, Portugal (Drs Borges and Neto); Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU, Leioa, Spain (Drs Miguelez and Ugedo); Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain (Drs Mico and Berrocoso); Neuropsychopharmacology and Psychobiology Research Group, Department of Psychology, University of Cádiz, Cádiz, Spain (Dr Berrocoso); Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain (Drs Mico and Berrocoso).
Luisa
L
Ugedo
Neuropsychopharmacology and Psychobiology Research Group, Department of Neuroscience, University of Cádiz, Cádiz, Spain (Drs Borges and Mico); Departamento de Biomedicina-Unidade de Biologia Experimental, da Faculdade de Medicina da Universidade do Porto (FMUP), Porto, Portugal (Drs Borges and Neto); Instituto de Biologia Molecular e Celular (IBMC) e Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, Porto, Portugal (Drs Borges and Neto); Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU, Leioa, Spain (Drs Miguelez and Ugedo); Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain (Drs Mico and Berrocoso); Neuropsychopharmacology and Psychobiology Research Group, Department of Psychology, University of Cádiz, Cádiz, Spain (Dr Berrocoso); Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain (Drs Mico and Berrocoso).
Esther
E
Berrocoso
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000607:Aminoacetonitrile / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology / Q000523:psychology*; D015331:Cohort Studies; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005620:Freund's Adjuvant; D008125:Locus Coeruleus / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D059225:Nociception / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000150:complications / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D011480:Protease Inhibitors; C424127:SL 327; D000607:Aminoacetonitrile; D005620:Freund's Adjuvant; D014446:Tyrosine 3-Monooxygenase; D048049:Extracellular Signal-Regulated MAP Kinases
ERK1/2; Locus Coeruleus; anxiety; arthritis; pain