title: Increased noradrenergic neurotransmission to a pain facilitatory area of the brain is implicated in facilitation of chronic pain.
abstract: BACKGROUND
  Noradrenaline reuptake inhibitors are known to produce analgesia through a spinal action but they also act in the brain. However, the action of noradrenaline on supraspinal pain control regions is understudied. The authors addressed the noradrenergic modulation of the dorsal reticular nucleus (DRt), a medullary pronociceptive area, in the spared nerve injury (SNI) model of neuropathic pain.
  
  
  METHODS
  The expression of the phosphorylated cAMP response element-binding protein (pCREB), a marker of neuronal activation, was evaluated in the locus coeruleus and A5 noradrenergic neurons (n = 6 rats/group). pCREB was studied in noradrenergic DRt-projecting neurons retrogradely labeled in SNI animals (n = 3). In vivo microdialysis was used to measure noradrenaline release in the DRt on nociceptive stimulation or after DRt infusion of clonidine (n = 5 to 6 per group). Pharmacology, immunohistochemistry, and western blot were used to study α-adrenoreceptors in the DRt (n = 4 to 6 per group).
  
  
  RESULTS
  pCREB expression significantly increased in the locus coeruleus and A5 of SNI animals, and most noradrenergic DRt-projecting neurons expressed pCREB. In SNI animals, noradrenaline levels significantly increased on pinprick (mean ± SD, 126 ± 14%; P = 0.025 vs. baseline) and acetone stimulation (mean ± SD, 151 ± 12%; P < 0.001 vs. baseline), and clonidine infusion showed decreased α2-mediated inhibitory function. α1-adrenoreceptor blockade decreased nociceptive behavioral responses in SNI animals. α2-adrenoreceptor expression was not altered.
  
  
  CONCLUSIONS
  Chronic pain induces brainstem noradrenergic activation that enhances descending facilitation from the DRt. This suggests that antidepressants inhibiting noradrenaline reuptake may enhance pain facilitation from the brain, counteracting their analgesic effects at the spinal cord.
authors.affiliation: From the Departamento de Biologia Experimental, Faculdade de Medicina, Universidade do Porto, Porto, Portugal (I.M., P.C., I.T.); Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal (I.M., P.C., I.T.); Department of Biomonitoring and Sensoring, University of Groningen, Groningen, The Netherlands (M.G.d.V., B.H.C.W.); Brains On-Line BV, Groningen, The Netherlands (M.G.d.V., B.H.C.W.); CINTESIS, Faculdade de Medicina, Universidade do Porto, Porto, Portugal (A.T.-P.); Screening and Test Evaluation Program, School of Public Health, The University of Sydney, New South Wales, Sydney, Australia (A.T.-P.); and Department of Pharmacology, Physiology and Neurosciences, University of South Carolina School of Medicine, Columbia, South Carolina (S.P.W.).
authors.forename: Isabel
authors.initials: I
authors.lastname: Martins
authors.forename: Paulina
authors.initials: P
authors.lastname: Carvalho
authors.forename: Martin G
authors.initials: MG
authors.lastname: de Vries
authors.forename: Armando
authors.initials: A
authors.lastname: Teixeira-Pinto
authors.forename: Steven P
authors.initials: SP
authors.lastname: Wilson
authors.forename: Ben H C
authors.initials: BH
authors.lastname: Westerink
authors.forename: Isaura
authors.initials: I
authors.lastname: Tavares
mesh_terms: D059331:Adrenergic Neurons / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D059350:Chronic Pain / Q000378:metabolism* / Q000473:pathology; D008125:Locus Coeruleus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008526:Medulla Oblongata / Q000378:metabolism* / Q000473:pathology; D009434:Neural Pathways / Q000378:metabolism / Q000473:pathology; D009437:Neuralgia / Q000378:metabolism* / Q000473:pathology; D009638:Norepinephrine / Q000378:metabolism*; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D009638:Norepinephrine