HIGH-INTENSITY SWIMMING EXERCISE REDUCES NEUROPATHIC PAIN IN AN ANIMAL MODEL OF COMPLEX REGIONAL PAIN SYNDROME TYPE I: EVIDENCE FOR A ROLE OF THE ADENOSINERGIC SYSTEM D. F. MARTINS, a,b,c  L. MAZZARDO-MARTINS, a,b  F. SOLDI, d J. STRAMOSK, c A. P. PIOVEZAN d AND A. R. S. SANTOS a,b * a Laborato ´rio de Neurobiologia da Dor e Inflamac ¸a ˜o, Departamento de Cie ˆncias Fisiolo ´gicas, Centro de Cie ˆncias Biolo ´ gicas, Universid- ade Federal de Santa Catarina, Campus Universita ´rio – Trindade, Floriano ´polis, SC, Brazil b Programa de Po ´ s-Graduac ¸a ˜o em Neurocie ˆncias, Centro de Cie ˆ ncias Biolo ´gicas, Universidade Federal de Santa Catarina, Campus Universita ´rio – Trindade, Floriano ´ polis, SC, Brazil c Curso de Fisioterapia, Universidade do Sul de Santa Catarina, Campus Grande Floriano ´polis – Palhoc ¸ a, SC, Brazil d Programa de Po ´ s-Graduac ¸a ˜o em Cie ˆncias da Sau ´de, Universidade do Sul de Santa Catarina, Tubara ˜o, SC, Brazil Abstract—This study investigated the involvement of the adenosinergic system in antiallodynia induced by exercise in an animal model of complex regional pain syndrome type I (CRPS-I). Furthermore, we analyzed the role of the opioid receptors on exercise-induced analgesia. Ischemia/reperfu- sion (IR) mice, nonexercised and exercised, received intra- peritoneal injections of caffeine (10 mg/kg, a non selective adenosine receptor antagonist), 1,3-dipropyl-8-cyclopentyl- xanthine (DPCPX) (0.1 mg/kg, a selective adenosine A 1 receptor antagonist), ZM241385 (3 mg/kg, a selective adeno- sine A 2A receptor antagonist), adenosine deaminase inhibi- tor erythro-9-(2-hydroxy-3nonyl) adenine [(EHNA), 5 mg/kg, an adenosine deaminase inhibitor] or naloxone (1 mg/kg, a nonselective opioid receptor antagonist). The results showed that high-intensity swimming exercise reduced mechanical allodynia in an animal model of CRPS-I in mice. The antiallodynic effect caused by exercise was reversed by pretreatment with caffeine, naloxone, DPCPX but it was not modified by ZM241385 treatment. In addition, treatment with EHNA, which suppresses the breakdown of adenosine to inosine, enhanced the pain-relieving effects of the high- intensity swimming exercise. This is the first report demon- strating that repeated sessions of high-intensity swimming exercise attenuate mechanical allodynia in an animal model of CRPS-I and that the mechanism involves endogenous adenosine and adenosine A 1 receptors. This study supports the use of high-intensity exercise as an adjunct therapy for CRPS-I treatment. Ó 2012 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: adenosine, analgesia, caffeine, CRPS-I, exercise. INTRODUCTION Chronic pain is a major health problem and one of the most frequent reasons for seeking medical care (Gureje et al., 1998; Schappert and Burt, 2006). Depending on its origin, chronic pain can be classified as inflammatory or neuropathic. Complex regional pain syndrome-I (CRPS-I) is a severe, disabling, and painful disease that may occur in an extremity after a trauma or injury; clinical features include spontaneous and stimulus- evoked pain, edema, vasomotor and sudomotor disturbances, motor dysfunction, and trophic changes. It is recognized as being difficult to treat, despite various methods of treatment being available, including physiotherapy, calcitonin, corticosteroids, sympathetic blockade, and non-steroidal anti-inflammatory drugs (Hord and Oaklander, 2003). During exercise, there is a high rate of ATP breakdown, which results in high tissue levels of adenosine (Bockman et al., 1975; Dworak et al., 2007; Roque et al., 2011). Many cell types produce adenosine, including neurons (Phillis, 1989), heart (Bacchus et al., 1982) and skeletal muscle (Bockman et al., 1975). Thus adenosine can overwhelm the purine catabolic pathway in the cell and the excess moves out, accumulating in the extracellular space and blood. High blood and extracellular levels of adenosine give this purine access to extracellular regulatory adenosine receptors, influencing the mechanisms of angiogenesis, blood flow, systolic blood pressure, respiration, plasma norepinephrine and epinephrine levels, through which it may exert various regulative effects on the body’s complex adaptation response to exercise. Adenosine has a half-life in the human blood of about 10 s (Klabunde, 1983) and can exert its effect through four distinct adenosine receptors (ARs) (A 1 ,A 2A ,A 2B and A 3 ), which are G-protein-coupled receptors. It is reformed into ATP via adenosine kinase, while excess 0306-4522/12 $36.00 Ó 2012 IBRO. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neuroscience.2012.12.042 * Corresponding author. Address: Departamento de Cieˆncias Fis- iolo´ gicas, Universidade Federal de Santa Catarina, Floriano´ polis, SC, Brazil. Tel: +55-48-3721-9444 (206); fax: +55-48-3721-9672. E-mail addresses: adair.santos@ufsc.br, adairrs.santos@gmail.com (A. R. S. Santos).   These authors equally contributed to this work. Abbreviations: ANOVA, analysis of variance; AR, adenosine receptor; CPIP, chronic post-ischemic pain; CRPS-I, complex regional pain syndrome type I; DMSO, dimethylsulfoxide; DPCPX, 1,3-dipropyl-8- cyclopentylxanthine; EHNA, erythro-9-(2-hydroxy-3nonyl) adenine; IMP, inosine monophosphate; IR, ischemia and reperfusion; SEM, standard error of the mean; ZM241385, 4-(2-[7-amino-2-(2- furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)-phenol. Neuroscience 234 (2013) 69–76 69