title: Role of brainstem serotonin in analgesia produced by low-intensity exercise on neuropathic pain after sciatic nerve injury in mice.
abstract: Physical exercise is a low-cost, safe, and efficient intervention for the reduction of neuropathic chronic pain in humans. However, the underlying mechanisms for how exercise reduces neuropathic pain are not yet well understood. Central monoaminergic systems play a critical role in endogenous analgesia leading us to hypothesize that the analgesic effect of low-intensity exercise occurs through activation of monoaminergic neurotransmission in descending inhibitory systems. To test this hypothesis, we induced peripheral nerve injury (PNI) by crushing the sciatic nerve. The exercise intervention consisted of low-intensity treadmill running for 2 weeks immediately after injury. Animals with PNI showed an increase in pain-like behaviors that were reduced by treadmill running. Reduction of serotonin (5-hydroxytryptamine) synthesis using the tryptophan hydroxylase inhibitor para-chlorophenylalanine methyl ester prevented the analgesic effect of exercise. However, blockade catecholamine synthesis with the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine had no effect. In parallel, 2 weeks of exercise increased brainstem levels of the 5-HT and its metabolites (5-hydroxyindoleacetic acid), decreased expression of the serotonin transporter, and increased expression of 5-HT receptors (5HT-1B, 2A, 2C). Finally, PNI-induced increase in inflammatory cytokines, tumor necrosis factor-alpha, and interleukin-1 beta, in the brainstem, was reversed by 2 weeks of exercise. These findings provide new evidence indicating that low-intensity aerobic treadmill exercise suppresses pain-like behaviors in animals with neuropathic pain by enhancing brainstem 5-HT neurotransmission. These data provide a rationale for the analgesia produced by exercise to provide an alternative approach to the treatment of chronic neuropathic pain.
authors.affiliation: Laboratory of Neurobiology of Pain and Inflammation, Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, Trindade, Florianopolis, Brazil Graduate Program in Neuroscience, Center of Biological Sciences, Federal University of Santa Catarina, Trindade, Florianopolis, Brazil Laboratory of Molecular and Behavioral Neurobiology, Department of Physiological Sciences, Federal University of Espírito Santo, Vitória, Brazil Department of Pharmacology, Federal University of Paraná, Curitiba, Brazil Department of Pharmacology, Center of Biological Sciences, Federal University of Santa Catarina, Trindade, Florianopolis, Brazil Department of Physical Therapy and Rehabilitation Science, Pain Research Program, University of Iowa, Iowa City, IA, USA.
authors.forename: Franciane
authors.initials: F
authors.lastname: Bobinski
authors.forename: Tamara A A
authors.initials: TAA
authors.lastname: Ferreira
authors.forename: Marina M
authors.initials: MM
authors.lastname: Córdova
authors.forename: Patrícia A
authors.initials: PA
authors.lastname: Dombrowski
authors.forename: Cláudio
authors.initials: C
authors.lastname: da Cunha
authors.forename: Caroline C do Espírito
authors.initials: CCDE
authors.lastname: Santo
authors.forename: Anicleto
authors.initials: A
authors.lastname: Poli
authors.forename: Rita G W
authors.initials: RGW
authors.lastname: Pires
authors.forename: Cristina
authors.initials: C
authors.lastname: Martins-Silva
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Sluka
authors.forename: Adair R S
authors.initials: ARS
authors.lastname: Santos
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001933:Brain Stem / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D010134:Fenclonine / Q000031:analogs & derivatives / Q000494:pharmacology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D009437:Neuralgia / Q000378:metabolism*; D059348:Peripheral Nerve Injuries / Q000378:metabolism*; D010805:Physical Conditioning, Animal; D011985:Receptors, Serotonin / Q000378:metabolism*; D012584:Sciatic Nerve / Q000293:injuries*; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors; D019805:alpha-Methyltyrosine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D011985:Receptors, Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C020261:4-chlorophenylalanine methyl ester; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D019805:alpha-Methyltyrosine; D014446:Tyrosine 3-Monooxygenase; D014365:Tryptophan Hydroxylase; D010134:Fenclonine