Regular Swimming Exercise Attenuated Neuroma Pain in Rats: Involvement of Leptin and Adiponectin

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The present study demonstrated that 5 weeks of regular swimming exercise alleviated both long-lasting neuroma pain at the lateral side of the ankle and allodynia at the hind paw plantar induced by TNT surgery. We further found that TNT surgery increased the leptin level in plasma and upregulated the expression of its receptor in neuroma, decreased the adiponectin level in plasma, and downregulated the expression of its receptor AdipoR1 in neuroma, whereas regular swimming exercise normalized these altered expressions. Moreover, our results showed local leptin injection at neuroma site dampened the analgesic effect of regular swimming exercise on neuroma pain, but local adiponectin administration at the neuroma site of TNT rats under sedentary conditions could alleviate the neuroma pain. Taken together, these findings provide evidence that regular exercise training attenuates neuroma pain by regulating the adipokines leptin and adiponectin.

In fact, the effects of both short-term exercise and regular exercise have been studied extensively in neuropathic pain models, which are relatively more common, such as spinal cord injury,13x13Detloff, MR, Smith, EJ, Quiros Molina, D, Ganzer, PD, and Houle, JD. Acute exercise prevents the development of neuropathic pain and the sprouting of non-peptidergic (GDNF- and artemin-responsive) c-fibers after spinal cord injury. Exp Neurol. 2014;
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,14x14Detloff, MR, Quiros-Molina, D, Javia, AS, Daggubati, L, Nehlsen, AD, Naqvi, A, Ninan, V, Vannix, KN, McMullen, MK, Amin, S, Ganzer, PD, and Houle, JD. Delayed exercise is ineffective at reversing aberrant nociceptive afferent plasticity or neuropathic pain after spinal cord injury in rats. Neurorehabil Neural Repair. 2016;
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spinal nerve ligation,50x50Stagg, NJ, Mata, HP, Ibrahim, MM, Henriksen, EJ, Porreca, F, Vanderah, TW, and Philip Malan, TJ. Regular exercise reverses sensory hypersensitivity in a rat neuropathic pain model role of endogenous opioids. Anesthesiology. 2011;
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Leptin is mainly produced by adipose tissue; extra-adipose leptin production is minimal under normal conditions, but it increases in certain pathologic processes, including inflammation.58x58Polyzos, SA and Mantzoros, CS. Leptin in health and disease: Facts and expectations at its twentieth anniversary. Metabolism. 2015;
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Adiponectin is also mainly secreted by adipocytes and it participates in glucose and lipid metabolism.27x27Ghadge, AA, Khaire, AA, and Kuvalekar, AA. Adiponectin: A potential therapeutic target for metabolic syndrome. Cytokine Growth Factor Rev. 2018;
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The effects of exercise training in animals with preexisting pain conditions have not been thoroughly studied. Swimming exercise fully reversed mechanical allodynia, alleviated thermal hyperalgesia, and normalized brain-derived neurotrophic factor upregulation and glial hyperactivity in a mouse model of neuropathic pain.1x1Almeida, C, DeMaman, A, Kusuda, R, Cadetti, F, Ravanelli, MI, Queiroz, AL, Sousa, TA, Zanon, S, Silveira, LR, and Lucas, G. Exercise therapy normalizes BDNF upregulation and glial hyperactivity in a mouse model of neuropathic pain. Pain. 2015;
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Notably, the pros and cons of exercise are intriguing questions in rodent models of pain,56x56Pitcher, MH. The impact of exercise in rodent models of chronic pain. Curr Osteoporos Rep. 2018;
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The intensity or the severity of perceived pain does not always correlate with the degree of tissue damage in the nervous system, and the importance of pain modulation by emotion has been widely recognized. In particular, stress could either suppress pain (stress-induced analgesia) or exacerbate it (stress-induced hyperalgesia), depending on the nature, duration, and intensity of the stressor.52x52Olango, WM and Finn, DP. Neurobiology of stress-induced hyperalgesia. Curr Top Behav Neurosci. 2014;
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