Exercise-Induced Hypoalgesia for Neuropathic Pain

Designing of effective treatments for neuropathic pain (NPP) has been hampered by the diversity of mechanisms and sites involved.¹ Randomized controlled trials have shown that only half of patients achieve pain relief with medication, most of whom still experience moderate-to-severe pain. In addition, NPP treatments are associated with adverse side effects which render treatments intolerable.²

A significant body of research using animal models of neuropathic pain suggests that exercise holds promise for the treatment of NPP.^3-5  A review recently published in Anatomical Science International, sought to clarify the mechanisms involved in exercise-induced hypoalgesia (EIH).⁶

Review author Katsuya Kami, PhD told Clinical Pain Advisor that elucidating the mechanisms underlying EIH would allow to develop new treatment methods for chronic pain, and to know novel pain inhibitory pathway. This review article highlights the “multiple factors and pain pathways which act to produce EIH […] we do not know the most important factor and pathway in producing EIH,” said Dr Kami.

Physical activity was shown to alleviate chronic pain experiences and improve functioning in human and animal studies.⁷

However, in the absence of  guidelines or clear understanding of  processes involved in EIH, healthcare providers may be hesitant to encourage physical activity in this population.

EIH is thought to occur peripherally. Exercise was shown to alleviate pain behaviors and reduce levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in rodents with induced sciatic nerve injury.7 These results suggest downregulation of pro-inflammatory cytokines may play a role in EIH.

In addition, pain leads to activation of M1 macrophages releasing pro-inflammatory cytokines, whereas pain relief is associated with the anti-inflammatory cytokines IL-10 and IL-4.^8,9

Following peripheral nerve injury, exercise resulted in reduced levels of IL-1β, IL-6 receptor, and BDNF in the dorsal horn and of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in the dorsal root ganglion.^10,11

According to other research, exercise may also contribute to hypoalgesia by inactivating glial cells in the dorsal horn, sustaining GABAergic inhibition and inhibition of histone deacetylases in the dorsal horn.^12,13

In the brainstem, exercise reverses pain behaviors and increases endogenous opioids, and one recent study found that treadmill running increased levels of serotonin and its receptors, while reducing expression of serotonin transporter in mice with sciatic nerve injuries.¹⁴ Such processes may be influential in producing EIH.

Though much more research is needed to fully understand the mechanisms involved in EIH for NPP, the current review highlights the most relevant studies on the topic. Clarifying these mechanisms “will allow a compelling argument to be made for exercise therapy with the goal of improving chronic pain,” wrote the authors.

Dr Kami and his colleagues are currently investigating the effects of the mesolimbic reward system in producing EIH.

References

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2. Dworkin RH, O’Connor, AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc. 2010; 85(3 Suppl): S3-S14.
3. Korb A, Bonetti LV, Silva SA, et al. Effect of treadmill exercise on serotonin immunoreactivity in medullary raphe nuclei and spinal cord following sciatic nerve transection in rats. Neurochem Res. 2010; 35: 380–389.
4. Sharma NK, Ryals JM, Gajewski BJ, Wright DE. Aerobic exercise alters analgesia and neurotrophin-3 synthesis in an animal model of chronic widespread pain. Phys Ther. 2010; 90: 714–725.
5. Stagg NJ^, Mata HP, Ibrahim MM, et al. Regular exercise reverses sensory hypersensitivity in a rat neuropathic pain model: role of endogenous opioids. Anesthesiol. 2011; 114: 940–948.

Kami K, Tajima F, Senba E. Exercise-induced hypoalgesia: potential mechanisms in animal models of neuropathic pain. Anat Sci Int. 2016; doi: 10.1007/s12565-016-0360-z

6. Kami K, Tajima F, Senba E. Exercise-induced hypoalgesia: potential mechanisms in animal models of neuropathic pain. Anat Sci Int. 2016; doi: 10.1007/s12565-016-0360-z
7. Chen YW, Li YT, Chen YC, Li ZY, Hung CH. Exercise training attenuates neuropathic pain and cytokine expression after chronic constriction injury of rat sciatic nerve. Anesth Analg. 2012;114(6):1330-7.
8. Hasegawa-moriyama M, Kurimoto T, Nakama M, et al. Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuates inflammatory pain through the induction of heme oxygenase-1 in macrophages. Pain. 2013;154(8):1402-12.
9. Grace PM, Hutchinson MR, Maier SF, Watkins LR. Pathological pain and the neuroimmune interface. Nat Rev Immunol. 2014;14(4):217-31.
10. Bobinski F, Martins DF, Bratti T, et al. Neuroprotective and neuroregenerative effects of low-intensity aerobic exercise on sciatic nerve crush injury in mice. Neuroscience. 2011;194:337-48.
11. López-Álvarez VM, Modol L, Navarro X, Cobianchi S. Early increasing-intensity treadmill exercise reduces neuropathic pain by preventing nociceptor collateral sprouting and disruption of chloride cotransporters homeostasis after peripheral nerve injury. Pain. 2015;156(9):1812-1825.
12. Kami K, Taguchi ms S, Tajima F, Senba E. Improvements in impaired GABA and GAD65/67 production in the spinal dorsal horn contribute to exercise-induced hypoalgesia in a mouse model of neuropathic pain. Mol Pain. 2016;12
13. Cherng CH, Lee KC, Chien CC, et al. Baicalin ameliorates neuropathic pain by suppressing HDAC1 expression in the spinal cord of spinal nerve ligation rats. J Formos Med Assoc. 2014;113(8):513-520. 
14. Gerin CG, Smith K, Hill S, Hill A, Madueke IC. Motor activity affects dopaminergic and noradrenergic systems of the dorsal horn of the rat lumbar spinal cord. Synapse. 2011;65(12):1282-1288.