title: Mice lacking central serotonergic neurons show enhanced inflammatory pain and an impaired analgesic response to antidepressant drugs.
abstract: A large body of literature has implicated serotonin [5-hydroxytryptamine (5-HT)] in descending modulation of nociceptive transmission. Here, we have studied the pain behavior of Lmx1b conditional knock-out mice (Lmx1b(f/f/p)), which lack 5-HT neurons in the CNS. Lmx1b(f/f/p) mutant mice showed normal thermal and visceral pain responses but were less sensitive to mechanical stimuli and exhibited enhanced inflammatory pain compared with their littermate control mice. Importantly, the analgesic effect of several antidepressant drugs, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants, was either abolished or greatly attenuated in Lmx1b(f/f/p) mice. Moreover, in the acute versus persistent pain settings, the analgesic actions of the SNRI duloxetine and the SSRI fluoxetine were differentially affected. Together, our results provide in vivo genetic evidence demonstrating that although the predominant role of the central 5-HT system in inflammatory pain is inhibitory, its role in acute mechanical pain is facilitatory. The findings that the analgesic effects of various antidepressant drugs are differentially dependent on the central 5-HT system should help us to understand the mechanism of the analgesic action of different classes of antidepressants in the management of persistent pain.
authors.affiliation: Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Zhong-Qiu
authors.initials: ZQ
authors.lastname: Zhao
authors.forename: Santina
authors.initials: S
authors.lastname: Chiechio
authors.forename: Yan-Gang
authors.initials: YG
authors.lastname: Sun
authors.forename: Kai-Hua
authors.initials: KH
authors.lastname: Zhang
authors.forename: Cheng-Shui
authors.initials: CS
authors.lastname: Zhao
authors.forename: Michael
authors.initials: M
authors.lastname: Scott
authors.forename: Randy L
authors.initials: RL
authors.lastname: Johnson
authors.forename: Evan S
authors.initials: ES
authors.lastname: Deneris
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Renner
authors.forename: Robert W
authors.initials: RW
authors.lastname: Gereau
authors.forename: Zhou-Feng
authors.initials: ZF
authors.lastname: Chen
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004487:Edema / Q000188:drug therapy / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D010146:Pain / Q000188:drug therapy* / Q000473:pathology; D010147:Pain Measurement / Q000379:methods; D012701:Serotonin / Q000172:deficiency*
chemical_list: D000700:Analgesics; D000928:Antidepressive Agents; D012701:Serotonin