title: Spinal cord stimulation modulates supraspinal centers of the descending antinociceptive system in rats with unilateral spinal nerve injury.
abstract: BACKGROUND
  The descending antinociceptive system (DAS) is thought to play crucial roles in the antinociceptive effect of spinal cord stimulation (SCS), especially through its serotonergic pathway. The nucleus raphe magnus (NRM) in the rostral ventromedial medulla is a major source of serotonin [5-hydroxytryptamine (5-HT)] to the DAS, but the role of the dorsal raphe nucleus (DRN) in the ventral periaqueductal gray matter is still unclear. Moreover, the influence of the noradrenergic pathway is largely unknown. In this study, we evaluated the involvement of these serotonergic and noradrenergic pathways in SCS-induced antinociception by behavioral analysis of spinal nerve-ligated (SNL) rats. We also investigated immunohistochemical changes in the DRN and locus coeruleus (LC), regarded as the adrenergic center of the DAS, and expression changes of synthetic enzymes of 5-HT [tryptophan hydroxylase (TPH)] and norepinephrine [dopamine β-hydroxylase (DβH)] in the spinal dorsal horn.
  
  
  RESULTS
  Intrathecally administered methysergide, a 5-HT1- and 5-HT2-receptor antagonist, and idazoxan, an α2-adrenergic receptor antagonist, equally abolished the antinociceptive effect of SCS. The numbers of TPH-positive serotonergic and phosphorylated cyclic AMP response element binding protein (pCREB)-positive neurons and percentage of pCREB-positive serotonergic neurons in the DRN significantly increased after 3-h SCS. Further, the ipsilateral-to-contralateral immunoreactivity ratio of DβH increased in the LC of SNL rats and reached the level seen in naïve rats, even though the number of pCREB-positive neurons in the LC was unchanged by SNL and SCS. Moreover, 3-h SCS did not increase the expression levels of TPH and DβH in the spinal dorsal horn.
  
  
  CONCLUSIONS
  The serotonergic and noradrenergic pathways of the DAS are involved in the antinociceptive effect of SCS, but activation of the DRN might primarily be responsible for this effect, and the LC may have a smaller contribution. SCS does not potentiate the synthetic enzymes of 5HT and norepinephrine in the neuropathic spinal cord.
authors.affiliation: Department of Anesthesiology, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan. negishieki@yahoo.co.jp.|Pain Mechanism Research Group, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan. negishieki@yahoo.co.jp.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Tazawa
authors.affiliation: Department of Neuroanatomy, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan. yoshinori.kamiya@gmail.com.|Pain Mechanism Research Group, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan. yoshinori.kamiya@gmail.com.|Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan. yoshinori.kamiya@gmail.com.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kamiya
authors.affiliation: Department of Anesthesiology, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan. ayako-kobayashi_829@hotmail.co.jp.
authors.forename: Ayako
authors.initials: A
authors.lastname: Kobayashi
authors.affiliation: Department of Neuroanatomy, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan. sibainuthounder@gmail.com.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Saeki
authors.affiliation: Department of Neuroanatomy, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan. takiguchi.masa@gmail.com.
authors.forename: Masahito
authors.initials: M
authors.lastname: Takiguchi
authors.affiliation: Department of Anesthesiology, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan. yusuke.nakahashi@gmail.com.|Pain Mechanism Research Group, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan. yusuke.nakahashi@gmail.com.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakahashi
authors.affiliation: Department of Anesthesiology, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan. sgonta@sea.plala.or.jp.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Shinbori
authors.affiliation: Department of Neuroanatomy, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan. funako@med.yokohama-cu.ac.jp.
authors.forename: Kengo
authors.initials: K
authors.lastname: Funakoshi
authors.affiliation: Department of Anesthesiology, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan. takigoto@yokohama-cu.ac.jp.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Goto
mesh_terms: D059331:Adrenergic Neurons / Q000187:drug effects / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000378:metabolism; D019329:Idazoxan / Q000494:pharmacology; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008784:Methysergide / Q000494:pharmacology; D059225:Nociception / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D059326:Serotonergic Neurons / Q000187:drug effects / Q000378:metabolism; D066148:Spinal Cord Dorsal Horn / Q000187:drug effects / Q000201:enzymology; D062187:Spinal Cord Stimulation / Q000379:methods*; D013127:Spinal Nerves / Q000187:drug effects / Q000293:injuries* / Q000473:pathology; D014365:Tryptophan Hydroxylase / Q000378:metabolism
chemical_list: D000700:Analgesics; D017362:Cyclic AMP Response Element-Binding Protein; D014365:Tryptophan Hydroxylase; D004299:Dopamine beta-Hydroxylase; D008784:Methysergide; D019329:Idazoxan