• Isabel Martins, Paulina Carvalho, Martin G de Vries, Armando Teixeira-Pinto, Steven P Wilson, Ben H C Westerink, and Isaura Tavares.
• 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.).
• Anesthesiology. 2015 Sep 1;123(3):642-53.

BackgroundNoradrenaline 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.MethodsThe 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).ResultspCREB 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.ConclusionsChronic 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.

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