RGD Reference Report - Amitriptyline induces nuclear transcription factor-kappaB-dependent glutamate transporter upregulation in chronic morphine-infused rats. - Rat Genome Database

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Amitriptyline induces nuclear transcription factor-kappaB-dependent glutamate transporter upregulation in chronic morphine-infused rats.

Authors: Tai, YH  Tsai, RY  Wang, YH  Cherng, CH  Tao, PL  Liu, TM  Wong, CS 
Citation: Tai YH, etal., Neuroscience. 2008 May 15;153(3):823-31. Epub 2008 Mar 6.
RGD ID: 2298784
Pubmed: PMID:18400403   (View Abstract at PubMed)
DOI: DOI:10.1016/j.neuroscience.2008.02.055   (Journal Full-text)

We previously showed that intrathecal co-administration of amitriptyline with morphine upregulates the expression of the glial glutamate transporters glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) and restores neuronal glutamate transporter excitatory amino acid carrier 1 (EAAC1) expression in chronically morphine-infused rats. The present study examined the role of nuclear transcription factor-kappaB (NF-kappaB) in the regulation of the expression of GLAST, GLT-1, and EAAC1 following long-term amitriptyline/morphine co-infusion. Male Wistar rats were implanted with two intrathecal catheters with or without a microdialysis probe; one of the catheters was used for continuous infusion of saline (control), morphine (15 mug/h), or morphine plus amitriptyline (both 15 mug/h) for 5 days, while the other was used for a single daily intrathecal injection of the NF-kappaB inhibitor Ro106-9920 (10 mul of 10 muM) for 5 days. We found that amitriptyline co-infusion restored the antinociceptive effect of morphine (4.5-fold right-shift in the morphine dose-response curve compared with a 65-fold right-shift in its absence) and this effect was inhibited by Ro106-9920 administration (48-fold right-shift). Moreover, amitriptyline/morphine co-infusion increased IkappaBalpha phosphorylation and the translocation of NF-kappaB p65 from the cytosol to the nucleus. Daily intrathecal injection of Ro106-9920 prevented the amitriptyline/morphine-induced NF-kappaB p65 translocation and reversed the amitriptyline/morphine-induced GLAST and GLT-1 upregulation and inhibited the restoration of EAAC1 expression. The Ro106-9920 injections abolished the inhibitory effect of amitriptyline on the morphine-evoked release of excitatory amino acids into the spinal cerebrospinal fluid (CSF) dialysates. In conclusion, amitriptyline/morphine co-infusion restores the antinociceptive effect of morphine and upregulates GLAST and GLT-1 expression and restores EAAC1 expression to baseline levels, thus reducing excitatory amino acid levels in the spinal CSF dialysates. The mechanism involves activation of the NF-kappaB pathway, but may also involve other pathways.




Biological Process

  
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Original Reference(s)
RelaRatresponse to morphine  IEP  RGD 


Genes (Rattus norvegicus)
Rela  (RELA proto-oncogene, NF-kB subunit)