Dataset Information

LPM580098, a Novel Triple Reuptake Inhibitor of Serotonin, Noradrenaline, and Dopamine, Attenuates Neuropathic Pain.

ABSTRACT: Background and Purpose: Sedation and somnolence remain serious adverse effects of the existing analgesics (e.g., pregabalin, duloxetine) for neuropathic pain. The available evidence indicates that serotonin (5-HT), noradrenaline (NE), and dopamine (DA) play important roles in modulating the descending inhibitory pain pathway and sleep-wake cycle. The aim of this work was to test the hypothesis that LPM580098, a novel triple reuptake inhibitor (TRI) of 5-HT, NE, and DA, has analgesic effect, and does not induce significant adverse effects associated with central inhibition, such as sedation and somnolence. Methods: The analgesic activity of LPM580098 was assessed on formalin test and spinal nerve ligation (SNL)-induced neuropathic pain model. Locomotor activity, pentobarbital sodium-induced sleeping and rota-rod tests were also conducted. In vitro binding and uptake assays, and Western blotting were performed to examine the potential mechanisms. Results: LPM580098 suppressed the nocifensive behaviors during phase II of the formalin test in mice. In SNL rats, LPM580098 (16 mg kg-1) inhibited mechanical allodynia, thermal hyperalgesia and hyperexcitation of wide-dynamic range (WDR) neurons, in which the effect of LPM580098 was similar to pregabalin (30 mg kg-1). However, pregabalin altered the spontaneous locomotion, affected pentobarbital sodium-induced sleep, and showed a trend to perform motor dysfunction, which were not induced by LPM580098. Mechanistically, LPM580098 inhibited the uptake of 5-HT, NE, and DA, improved pain-induced changes of the synaptic functional plasticity and structural plasticity possibly via downregulating the NR2B/CaMKII?/GluR1 and Rac1/RhoA signaling pathways. Conclusion: Our results suggest that LPM580098, a novel TRI, is effective in attenuating neuropathic pain without producing unwanted sedation and somnolence associated with central nervous system (CNS) depressants.

SUBMITTER: Li N

PROVIDER: S-EPMC6382704 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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LPM580098, a Novel Triple Reuptake Inhibitor of Serotonin, Noradrenaline, and Dopamine, Attenuates Neuropathic Pain.

Li Nannan N Li Chunmei C Han Rui R Wang Yu Y Yang Mina M Wang Hongbo H Tian Jingwei J

Frontiers in pharmacology 20190214

<b>Background and Purpose:</b> Sedation and somnolence remain serious adverse effects of the existing analgesics (e.g., pregabalin, duloxetine) for neuropathic pain. The available evidence indicates that serotonin (5-HT), noradrenaline (NE), and dopamine (DA) play important roles in modulating the descending inhibitory pain pathway and sleep-wake cycle. The aim of this work was to test the hypothesis that LPM580098, a novel triple reuptake inhibitor (TRI) of 5-HT, NE, and DA, has analgesic effec ...[more]

PMID: 30837867

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Project description:Importance:In 2006, the US Food and Drug Administration (FDA) issued an advisory warning on the risk of serotonin syndrome with concomitant use of triptans and selective serotonin reuptake inhibitor (SSRI) or selective norepinephrine reuptake inhibitor (SNRI) antidepressants, but the true risk of serotonin syndrome in these patients remains unknown. Objective:To assess the risk of serotonin syndrome with concomitant use of triptans and SSRI or SNRI antidepressants. Design, Setting, and Participants:This study used electronic health record data from the Partners Research Data Registry (RPDR) to identify patients who had received an International Classification of Diseases, Ninth Revision diagnosis compatible with serotonin syndrome who had been coprescribed triptans and SSRI or SNRI antidepressants in the Greater Boston, Massachusetts, area from January 1, 2001, through December 31, 2014 (14 years). Clinical information was extracted to determine whether the case met formal diagnostic criteria and had coprescription within a calendar year. Both conservative and broad case definitions were used to better characterize the spectrum of risk. Data analysis was performed from November 23, 2016, to July 15, 2017. Main Outcomes and Measures:Incidence of serotonin syndrome. Results:The RPDR search revealed 47?968 (±3) unique patients who were prescribed triptans during the 14-year period of the study. A total of 19?017 (±3) patients were coprescribed triptans and antidepressants during the study, with a total of 30?928 person-years of exposure. Serotonin syndrome was suspected in 17 patients. Only 2 patients were classified as having definite serotonin syndrome (incidence rate, 0.6 cases per 10?000 person-years of exposure; 95% CI, 0.0-1.5). Five patients were classified as having possible serotonin syndrome (incidence rate with these 5 cases added to the 2 definite cases, 2.3 cases per 10?000 person-years of exposure; 95% CI, 0.6-3.9). The proportion of patients with triptan prescriptions who were coprescribed an SSRI or SNRI antidepressant was relatively stable during the study, ranging from 21% to 29%. Conclusions and Relevance:The risk of serotonin syndrome associated with concomitant use of triptans and SSRIs or SNRIs was low. Coprescription of these drugs is common and did not decrease after the 2006 FDA advisory. Our results cast doubt on the validity of the FDA advisory and suggest that it should be reconsidered.

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Dataset Information

LPM580098, a Novel Triple Reuptake Inhibitor of Serotonin, Noradrenaline, and Dopamine, Attenuates Neuropathic Pain.

Publications

LPM580098, a Novel Triple Reuptake Inhibitor of Serotonin, Noradrenaline, and Dopamine, Attenuates Neuropathic Pain.

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