title: Evaluation of the analgesic effects of ammoxetine, a novel potent serotonin and norepinephrine reuptake inhibitor.
abstract: OBJECTIVE
  The selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors (SNRIs) are commonly used for the treatment of neuropathic pain and fibromyalgia. Ammoxetine ((±)-3-(benzo[d] [1,3]dioxol-4-yloxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine) has been identified as a novel potent SNRI. In this study, we evaluated the acute analgesic properties of ammoxetine in different animal models of pain, and examined the involvement of monoamines in its analgesic actions.
  
  
  METHODS
  The analgesic effects of ammoxetine were assayed using models of acetic acid- and formalin-induced pain in mice, neuropathic pain induced by sciatic nerve injury (SNI), chronic constriction injury (CCI) and reserpine-induced fibromyalgia pain in rats. The contents of 5-HT and NE in brain regions of fibromyalgia rats were measured using HPLC-ECD. In all the experiments, duloxetine was used as a positive control drug.
  
  
  RESULTS
  Oral administration of ammoxetine (0.625-10 mg/kg) or duloxetine (2.5-40 mg/kg) dose-dependently decreased the number of acetic acid-induced writhing and formalin-induced first phase and second phase paw licking time in mice. Oral administration of ammoxetine (2.5-10 mg/kg) or duloxetine (10 mg/kg) alleviated mechanical allodynia in SNI and CCI rats and thermal hyperalgesia in CCI rats. The antiallodynic effect of ammoxetine in CCI rats was abolished by pretreatment with para-chlorophenylalanine methyl ester hydrochloride (PCPA, a 5-HT synthesis inhibitor) or α-methyl-para-tyrosine methylester (AMPT, a catecholamine synthesis inhibitor). Oral administration of ammoxetine (30 mg/kg) or duloxetine (50 mg/kg) significantly attenuated tactile allodynia in rats with reserpine-induced fibromyalgia. In the fibromyalgia rats, administration of ammoxetine (10, 30 mg/kg) or duloxetine (30, 50 mg/kg) dose-dependently increased the levels of 5-HT and NE, and decreased the metabolite ratio of 5-HT (5-HIAA/5-HT) in the spinal cord, hypothalamus, thalamus and prefrontal cortex.
  
  
  CONCLUSIONS
  Ammoxetine effectively alleviates inflammatory, continuous, neuropathic and fibromyalgia-related pain in animal models, which can be attributed to enhanced neurotransmission of 5-HT and NE in the descending inhibitory systems.
authors.affiliation: Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Xue
authors.affiliation: Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Qiong-Yin
authors.initials: QY
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Bo-Hua
authors.initials: BH
authors.lastname: Zhong
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors.forename: Cai-Ying
authors.initials: CY
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: You-Zhi
authors.initials: YZ
authors.lastname: Zhang
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D052117:Benzodioxoles / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005356:Fibromyalgia / Q000188:drug therapy*; D006930:Hyperalgesia / Q000188:drug therapy*; D008297:Male; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D011437:Propylamines / Q000008:administration & dosage / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D045442:Rotarod Performance Test; D020426:Sciatic Neuropathy / Q000188:drug therapy*; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D018712:Analgesics, Non-Narcotic; D052117:Benzodioxoles; D011437:Propylamines; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; C000614911:ammoxetine