title: Differential and synergistic effects of selective norepinephrine and serotonin reuptake inhibitors in rodent models of pain.
abstract: There is increasing recognition that norepinephrine (NE) and serotonin (5-HT) reuptake inhibitors (NRIs and SRIs) are efficacious in treating some types of pain. To date, studies have not systematically evaluated the relative activity at the NE and/or 5-HT transporter required for maximal efficacy in rodent pain models. Known selective NE and 5-HT reuptake inhibitors reboxetine, desipramine, fluoxetine, and paroxetine were evaluated in both in vitro and in vivo assays. Using the spinal nerve ligation model of neuropathic pain, the compounds differentially reversed tactile allodynia. Evaluation of a broader spectrum of reuptake inhibitors in the para-phenylquinone (PPQ)-induced abdominal constriction model, a model of acute visceral pain, demonstrated that both the SRIs and the NRIs significantly blocked abdominal constrictions. However, the magnitude of this effect was greater following treatment with compounds having greater affinity for NRI compared with SRI affinity. In addition, isobolographic analyses indicated significant synergistic effects for all combinations of desipramine and fluoxetine in the PPQ model of visceral pain. Collectively, the present results support the hypothesis that compounds with greater NRI activity should be more effective for the treatment of pain than compounds having only SRI activity, and this hypothesis is also supported by clinical data. These studies also suggest that the potency and effectiveness of NRIs might be enhanced by the presence of 5-HT activity.
authors.affiliation: Wyeth Research, Neuroscience Discovery Research, Princeton, NJ 08543, USA. leventl@wyeth.com
authors.forename: Liza
authors.initials: L
authors.lastname: Leventhal
authors.forename: Valerie
authors.initials: V
authors.lastname: Smith
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Hornby
authors.forename: Terrance H
authors.initials: TH
authors.lastname: Andree
authors.forename: Michael R
authors.initials: MR
authors.lastname: Brandt
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Rogers
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009638:Norepinephrine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011941:Receptors, Adrenergic / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D018712:Analgesics, Non-Narcotic; D009638:Norepinephrine; D011941:Receptors, Adrenergic; D011985:Receptors, Serotonin; D017367:Selective Serotonin Reuptake Inhibitors