title: Effects of milnacipran, a 5-HT and noradrenaline reuptake inhibitor, on C-fibre-evoked field potentials in spinal long-term potentiation and neuropathic pain.
abstract: OBJECTIVE
  The analgesic action of 5-HT and noradrenaline reuptake inhibitors (SNRIs) on nociceptive synaptic transmission in the spinal cord is poorly understood. We investigated the effects of milnacipran, an SNRI, on C-fibre-evoked field potentials (FPs) in spinal long-term potentiation (LTP), a proposed synaptic mechanism of hypersensitivity, and on the FPs in a neuropathic pain model.
  
  
  METHODS
  C-fibre-evoked FPs by electrical stimulation of the sciatic nerve fibres were recorded in the spinal dorsal horn of anaesthetized adult rats, and LTP was induced by high-frequency stimulation of the sciatic nerve fibres. A rat model of neuropathic pain was produced by L5 spinal nerve ligation and transection.
  
  
  RESULTS
  Milnacipran produced prolonged inhibition of C-fibre-evoked FPs when applied spinally after the establishment of LTP of C-fibre-evoked FPs in naïve animals. In the neuropathic pain model, spinal administration of milnacipran clearly reduced the basal C-fibre-evoked FPs. These inhibitory effects of milnacipran were blocked by spinal administration of methysergide, a 5-HT½ receptor antagonist, and yohimbine or idazoxan, α₂-adrenoceptor antagonists. However, spinal administration of milnacipran in naïve animals did not affect the basal C-fibre-evoked FPs and the induction of spinal LTP.
  
  
  CONCLUSIONS
  Milnacipran inhibited C-fibre-mediated nociceptive synaptic transmission in the spinal dorsal horn after the establishment of spinal LTP and in the neuropathic pain model, by activating both spinal 5-hydroxytryptaminergic and noradrenergic systems. The condition-dependent inhibition of the C-fibre-mediated transmission by milnacipran could provide novel evidence regarding the analgesic mechanisms of SNRIs in chronic pain.
authors.affiliation: Laboratory of CNS Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ohnami
authors.forename: A
authors.initials: A
authors.lastname: Kato
authors.forename: K
authors.initials: K
authors.lastname: Ogawa
authors.forename: S
authors.initials: S
authors.lastname: Shinohara
authors.forename: H
authors.initials: H
authors.lastname: Ono
authors.forename: M
authors.initials: M
authors.lastname: Tanabe
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D003521:Cyclopropanes / Q000494:pharmacology*; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D005071:Evoked Potentials / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D000078764:Milnacipran; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D018759:Adrenergic Uptake Inhibitors; D003521:Cyclopropanes; D000078764:Milnacipran; D017367:Selective Serotonin Reuptake Inhibitors