Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=27315512
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Gabapentin loses efficacy over time after nerve injury in rats: role of glutamate
transporter-1 in the locus coeruleus
#MMPMID27315512
Kimura M
; Eisenach JC
; Hayashida KI
Pain
2016[Sep]; 157
(9
): 2024-2032
PMID27315512
show ga
Despite being one of the first-choice analgesics for chronic neuropathic pain,
gabapentin sometimes fails to provide analgesia, but the mechanisms for this lack
of efficacy is unclear. Rats with nerve injury including L5-L6 spinal nerve
ligation (SNL) respond uniformly and well to gabapentin, but many of these
studies are performed within just a few weeks of injury, questioning their
relevance to chronic neuropathic pain. In this study, intraperitoneal gabapentin
showed a time-dependently reduction in antihypersensitivity after SNL, associated
with downregulation of astroglial glutamate transporter-1 (GLT-1) in the locus
coeruleus (LC). Consistently, SNL also time-dependently increased basal but
masked gabapentin-induced noradrenergic neuronal activity in the LC. In rats 2
weeks after SNL, knock-down of GLT-1 in the LC reduced the antihypersensitivity
effect of gabapentin. In rats 8 weeks after SNL, increasing GLT-1 expression by
histone deacetylase inhibitor valproate restored the antihypersensitivity effect
of gabapentin, associated with restored gabapentin-induced noradrenergic neuronal
activity in the LC and subsequent spinal noradrenaline release. Knock-down of
GLT-1 in the LC reversed the effect of valproate to restore gabapentin-induced
antihypersensitivity. In addition, the antihypersensitivity effect of the
intrathecal ?2-adrenoceptor agonist clonidine also decreased with time after SNL
injury. These results suggest that downregulation of GLT-1 in the LC and reduced
spinal noradrenergic inhibition contribute to impaired analgesic efficacy from
gabapentin in chronic neuropathic pain and that valproate can rescue this
impaired efficacy.
|Amines/*therapeutic use
[MESH]
|Analgesics/*therapeutic use
[MESH]
|Animals
[MESH]
|Antihypertensive Agents/pharmacology
[MESH]
|Atropine/pharmacology
[MESH]
|Bronchodilator Agents/pharmacology
[MESH]
|CREB-Binding Protein/metabolism
[MESH]
|Clonidine/pharmacology
[MESH]
|Cyclohexanecarboxylic Acids/*therapeutic use
[MESH]
free
free
free
