Mice lacking central serotonergic neurons show enhanced inflammatory pain and an impaired analgesic response to antidepressant drugs.
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.
Zhao
Zhong-Qiu
ZQ
Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Chiechio
Santina
S
Sun
Yan-Gang
YG
Zhang
Kai-Hua
KH
Zhao
Cheng-Shui
CS
Scott
Michael
M
Johnson
Randy L
RL
Deneris
Evan S
ES
Renner
Kenneth J
KJ
Gereau
Robert W
RW
Chen
Zhou-Feng
ZF
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*
D000700:Analgesics; D000928:Antidepressive Agents; D012701:Serotonin