Role of brainstem serotonin in analgesia produced by low-intensity exercise on neuropathic pain following sciatic nerve injury in mice

• Published in: Pain (Amsterdam) Vol. 156; no. 12; pp. 2595 - 2606
• Main Authors: Bobinski, Franciane, Ferreira, Tamara Andrea Alarcón, Córdova, Marina Machado, Dombrowski, Patrícia Andréia, da Cunha, Cláudio, Santo, Caroline Cunha do Espírito, Poli, Anicleto, Pires, Rita Gomes Wanderley, Martins-Silva, Cristina, Sluka, Kathleen Anne, Santos, Adair Roberto Soares
• Format: Journal Article
• Language: English
• Published: 01-12-2015
• ISSN: 0304-3959; 1872-6623
• DOI: 10.1097/j.pain.0000000000000372

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 two weeks immediately after injury. Animals with PNI showed an increase in pain-like behaviors that were reduced by treadmill running. Reduction of serotonin (5-HT) synthesis using the tryptophan hydroxylase inhibitor PCPA prevented the analgesic effect of exercise. However, blockade catecholamine synthesis with the tyrosine hydroxylase inhibitor AMPT had no effect. In parallel, 2 weeks of exercise increased brainstem levels of the 5-HT and its metabolites (5-HIAA), decreased expression of the serotonin transporter (SERT), and increased expression of 5-HT receptors (5HT-
1B, 2A, 2C).
Lastly, PNI-induced increased in inflammatory cytokines, TNF-α and IL-1β, 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.