title: Excitatory effect of Neurotropin(®) on noradrenergic neurons in rat locus coeruleus.
abstract: OBJECTIVE
  Although the clinical use of Neurotropin® as an analgesic for chronic pain has been firmly established, its analgesic mechanism is still unclear. In this study, we investigate the direct effects of Neurotropin using an electrophysiological method.
  
  
  METHODS
  Blind patch-clamp recordings were made from rat locus coeruleus (LC) and periaqueductal gray (PAG) neurons in brainstem slices of normal rats. The effects of intracerebroventricular (icv) injection of Neurotropin on nociceptive transmission were recorded from spinal substantia gelatinosa (SG) neurons in fifth lumbar spinal nerve-ligated (L5-SNL) rats using an in vivo patch-clamp method.
  
  
  RESULTS
  Neurotropin (0.2–1.0 NU/mL) dose-dependently increased the firing rate in noradrenergic LC neurons of normal rats. Under the voltage-clamp condition, Neurotropin induced an inward current in 90% of LC neurons thatwas not affected by tetrodotoxin or an injection of GDP-β-S (G protein inhibitor) through recording pipettes. In contrast, Neurotropin had no effects on all PAG neurons tested. Using in vivo patch-clamp recordings, the icv injection of Neurotropin inhibited both frequency and amplitude of pinch-evoked excitatory postsynaptic currents of SG neurons in L5-SNL rats. These results suggest that Neurotropin directly excites the descending noradrenergic LC neurons and inhibits nociceptive transmission in the spinal dorsal horn.
  
  
  CONCLUSIONS
  This study is the first direct demonstration that Neurotropin activates the noradrenergic descending pain inhibitory systems, and this would reinforce the usefulness of Neurotropin in the treatment of human neuropathic pain.
authors.affiliation: Department of Pharmacological Research, Institute of Bio-Active Science, Nippon Zoki Pharmaceutical Co., Ltd., 442-1, Kinashi, Kato, Hyogo 673-1461, Japan. Electronic address: h-okai@nippon-zoki.co.jp.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Okai
authors.affiliation: Department of Pharmacological Research, Institute of Bio-Active Science, Nippon Zoki Pharmaceutical Co., Ltd., 442-1, Kinashi, Kato, Hyogo 673-1461, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Okazaki
authors.affiliation: Department of Pharmacological Research, Institute of Bio-Active Science, Nippon Zoki Pharmaceutical Co., Ltd., 442-1, Kinashi, Kato, Hyogo 673-1461, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Kawamura
authors.affiliation: Graduate School of Health Sciences, Kumamoto Health Science University, Kumamoto 861-5598, Japan.
authors.forename: Megumu
authors.initials: M
authors.lastname: Yoshimura
mesh_terms: D059331:Adrenergic Neurons / Q000187:drug effects / Q000502:physiology*; D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D004353:Drug Evaluation, Preclinical; D007276:Injections, Intraventricular; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects*; D008297:Male; D009437:Neuralgia / Q000188:drug therapy; D059225:Nociception / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010487:Periaqueductal Gray / Q000166:cytology / Q000187:drug effects; D011134:Polysaccharides / Q000008:administration & dosage*; D017207:Rats, Sprague-Dawley
chemical_list: D000700:Analgesics; D011134:Polysaccharides; C010491:neurotropin
keywords: Descending pain inhibitory system; In vivo patch clamp; Locus coeruleus; Neuropathic pain; Neurotropin; Noradrenaline