title: Electroacupuncture Enhances the Antiallodynic and Antihyperalgesic Effects of Milnacipran in Neuropathic Rats.
abstract: BACKGROUND
  Milnacipran, a selective serotonin/norepinephrine-reuptake inhibitor, has been shown to elicit a beneficial effect in various models of neuropathic pain. Previously, we reported that repetitive electroacupuncture (EA) significantly ameliorates neuropathic pain induced by L5 spinal nerve ligation (SNL). In the present study, we sought to determine whether a single treatment with EA produces analgesia and whether EA in combination with a subeffective dosage of milnacipran exhibits an additive effect in SNL rats.
  
  
  METHODS
  Mechanical allodynia and thermal hyperalgesia were assessed by measuring paw withdrawal thresholds and latencies in response to mechanical and thermal stimuli, respectively, 1 day before and 5 days after neuropathic surgery. In addition, on day 5 post-SNL, time courses of behaviors were assessed at 0, 1, 2, 4, 6, and 8 hours after intrathecal (i.t.) milnacipran (1, 5, and 20 μg) administration. EA (10 Hz/1 mA) was administered at the ST36 and GB34 acupoints for 30 minutes on day 5 and the time courses of behaviors were also assessed at 0, 1, 2, 4, 6, and 8 hours later. Similarly, when treated in combination (milnacipran [5 μg, i.t.] and EA [10 Hz/1 mA]), time courses of behaviors were assessed at the same time points.
  
  
  RESULTS
  Intrathecal injection of milnacipran at 5 or 20 μg exerted dose-dependent effects on thermal hyperalgesia but had similar efficacies on mechanical allodynia. Furthermore, EA itself detectably attenuated hyperalgesia at 4 hours after the application, but no statistically significant difference was found in mechanical allodynia. Importantly, cotreatment with EA and milnacipran (5 μL) produced more potent antiallodynic and antihyperalgesic effects than those obtained from EA or milnacipran alone at 1, 2, and 4 hours after treatment, indicating an additive effect. In addition, the analgesic effect of EA plus milnacipran was almost completely abolished by the catecholamine neurotoxin 6-hydroxydopamine hydrobromide (25 μg), which depletes spinal norepinephrine, and by yohimbine (an α2-adrenoceptor antagonist, 30 μg, i.t.). Somewhat surprisingly, the analgesic effect of milnacipran plus EA lasted for 6 hours.
  
  
  CONCLUSIONS
  The study shows that, in male rats with SNL, spinal administration of milnacipran effectively alleviates mechanical allodynia and thermal hyperalgesia, and that a single treatment of EA has an antihyperalgesic effect. Furthermore, our findings suggest that coapplication of EA and milnacipran enhanced antiallodynia and antihyperalgesia by activating spinal noradrenergic systems coupled with spinal α2-adrenoceptors and prolongs the duration of analgesia.
authors.affiliation: From the *Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Korea; †Department of Ophthalmology and Otolaryngology and Dermatology, School of Korean Medicine, Pusan National University, Yangsan, Korea; and ‡Department of Korean Medical Science and Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Yangsan, Korea.
authors.forename: Chengjin
authors.initials: C
authors.lastname: Li
authors.forename: Byeong Uk
authors.initials: BU
authors.lastname: Ji
authors.forename: Yiquot
authors.initials: Y
authors.lastname: Kim
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Nam-Kwen
authors.initials: NK
authors.lastname: Kim
authors.forename: Seung Tae
authors.initials: ST
authors.lastname: Kim
authors.forename: Sungtae
authors.initials: S
authors.lastname: Koo
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003131:Combined Modality Therapy; D003521:Cyclopropanes / Q000494:pharmacology*; D004195:Disease Models, Animal; D015671:Electroacupuncture; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology / Q000523:psychology / Q000628:therapy*; D008297:Male; D000078764:Milnacipran; D009043:Motor Activity / Q000187:drug effects; D009437:Neuralgia / Q000188:drug therapy / Q000503:physiopathology / Q000523:psychology / Q000628:therapy*; D017288:Pain Threshold / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000700:Analgesics; D003521:Cyclopropanes; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D000078764:Milnacipran