title: Early transcutaneous electrical nerve stimulation reduces hyperalgesia and decreases activation of spinal glial cells in mice with neuropathic pain.
abstract: Although transcutaneous electrical nerve stimulation (TENS) is widely used for the treatment of neuropathic pain, its effectiveness and mechanism of action in reducing neuropathic pain remain uncertain. We investigated the effects of early TENS (starting from the day after surgery) in mice with neuropathic pain, on hyperalgesia, glial cell activation, pain transmission neuron sensitization, expression of proinflammatory cytokines, and opioid receptors in the spinal dorsal horn. Following nerve injury, TENS and behavioral tests were performed every day. Immunohistochemical, immunoblot, and flow cytometric analysis of the lumbar spinal cord were performed after 8 days. Early TENS reduced mechanical and thermal hyperalgesia and decreased the activation of microglia and astrocytes (P<0.05). In contrast, the application of TENS at 1 week (TENS-1w) or 2 weeks (TENS-2w) after injury was ineffective in reducing hyperalgesia (mechanical and thermal) or activation of microglia and astrocytes. Early TENS decreased p-p38 within microglia (P<0.05), the expression levels of protein kinase C (PKC-γ), and phosphorylated anti-phospho-cyclic AMP response element-binding protein (p-CREB) in the superficial spinal dorsal horn neurons (P<0.05), mitogen-activated protein (MAP) kinases, and proinflammatory cytokines, and increased the expression levels of opioid receptors (P<0.05). The results suggested that the application of early TENS relieved hyperalgesia in our mouse model of neuropathic pain by inhibiting glial activation, MAP kinase activation, PKC-γ, and p-CREB expression, and proinflammatory cytokines expression, as well as maintenance of spinal opioid receptors. The findings indicate that TENS treatment is more effective when applied as early after nerve injury as possible.
authors.affiliation: Division of Physical Therapy and Rehabilitation Medicine, University of Fukui Hospital, Fukui, Japan Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan Pain Research Center, Kansai University of Health Sciences, Kumatori, Osaka 590-0482, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Matsuo
authors.forename: Kenzo
authors.initials: K
authors.lastname: Uchida
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakajima
authors.forename: Alexander Rodriguez
authors.initials: AR
authors.lastname: Guerrero
authors.forename: Shuji
authors.initials: S
authors.lastname: Watanabe
authors.forename: Naoto
authors.initials: N
authors.lastname: Takeura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sugita
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Shimada
authors.forename: Terumasa
authors.initials: T
authors.lastname: Nakatsuka
authors.forename: Hisatoshi
authors.initials: H
authors.lastname: Baba
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D006930:Hyperalgesia / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009437:Neuralgia / Q000378:metabolism / Q000628:therapy*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010812:Physical Stimulation; D011957:Receptors, Opioid / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D004561:Transcutaneous Electric Nerve Stimulation
chemical_list: D016207:Cytokines; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D009270:Naloxone
keywords: Microglia; Neuropathic pain; Opioid receptor; P38 MAPK; Spinal cord; Transcutaneous electrical nerve stimulation (TENS)