TY - JOUR
T1 - Dexamethasone modulates the development of morphine tolerance and expression of glutamate transporters in rats
AU - Wen, Z. H.
AU - Wu, G. J.
AU - Chang, Y. C.
AU - Wang, J. J.
AU - Wong, C. S.
PY - 2005
Y1 - 2005
N2 - We recently demonstrated an increase in spinal cerebrospinal fluid (CSF) excitatory amino acids (EAAs) in morphine-tolerant rats after morphine challenge. The present study examined whether co-infusion of the glucocorticoid dexamethasone (DEX) co-infusion inhibited morphine tolerance and the morphine challenge-induced EAAs increase after long-term morphine infusion. Intrathecal (i.t.) catheters and one microdialysis probe were implanted to male Wistar rats. Rats were divided into four groups: i.t. morphine (15μg/h), saline (1μl/h), DEX (2μg/h), or DEX (2μg/h) plus morphine (15μg/h) infusion for 5 days. Tail-flick responses were examined before drug infusion and daily after the start of infusion for 5 days. Moreover, on day 5 after morphine challenge (50μg, i.t.), CSF EAAs was also measured. Rat spinal cords were removed on day 5, and prepared for Western blot analysis of different glutamate transporters (GTs). The AD50 (analgesic dose) on day 5 was 1.33μg in saline-infused rats, 83.84μg in morphine-tolerant rats, and 10.15μg in DEX plus morphine co-infused rats. Single DEX (2μg, i.t.) injection did not enhance morphine's antinociceptive effect in either naïve or morphine-tolerant rats. No difference in CSF EAA level was observed in all groups between baseline (before drug infusion) and on day 5 after tolerance developed. Surprisingly, on day 5, after morphine challenge, an increase in glutamate and aspartate (284±47% and 201±18% of basal) concentration was observed, and morphine lost its antinociceptive effect (maximum percent effect, MPE=41±12%), whereas DEX/morphine co-infusion inhibited morphine-evoked EAA increase with a MPE=97±2%. DEX co-infusion prevented the downregulation of glial glutamate transporters (GLAST (Glu-Asp transporter) and GLT-1 (Glu transporter-1)), but not the neuronal GT EAAC1 (excitatory amino acid carrier). Upregulation of GLT-1 was also observed (204±20% of basal). DEX co-infusion inhibits the morphine-challenge induced EAA increase and prevents the loss of morphine's antinociceptive effect after long-term morphine infusion.
AB - We recently demonstrated an increase in spinal cerebrospinal fluid (CSF) excitatory amino acids (EAAs) in morphine-tolerant rats after morphine challenge. The present study examined whether co-infusion of the glucocorticoid dexamethasone (DEX) co-infusion inhibited morphine tolerance and the morphine challenge-induced EAAs increase after long-term morphine infusion. Intrathecal (i.t.) catheters and one microdialysis probe were implanted to male Wistar rats. Rats were divided into four groups: i.t. morphine (15μg/h), saline (1μl/h), DEX (2μg/h), or DEX (2μg/h) plus morphine (15μg/h) infusion for 5 days. Tail-flick responses were examined before drug infusion and daily after the start of infusion for 5 days. Moreover, on day 5 after morphine challenge (50μg, i.t.), CSF EAAs was also measured. Rat spinal cords were removed on day 5, and prepared for Western blot analysis of different glutamate transporters (GTs). The AD50 (analgesic dose) on day 5 was 1.33μg in saline-infused rats, 83.84μg in morphine-tolerant rats, and 10.15μg in DEX plus morphine co-infused rats. Single DEX (2μg, i.t.) injection did not enhance morphine's antinociceptive effect in either naïve or morphine-tolerant rats. No difference in CSF EAA level was observed in all groups between baseline (before drug infusion) and on day 5 after tolerance developed. Surprisingly, on day 5, after morphine challenge, an increase in glutamate and aspartate (284±47% and 201±18% of basal) concentration was observed, and morphine lost its antinociceptive effect (maximum percent effect, MPE=41±12%), whereas DEX/morphine co-infusion inhibited morphine-evoked EAA increase with a MPE=97±2%. DEX co-infusion prevented the downregulation of glial glutamate transporters (GLAST (Glu-Asp transporter) and GLT-1 (Glu transporter-1)), but not the neuronal GT EAAC1 (excitatory amino acid carrier). Upregulation of GLT-1 was also observed (204±20% of basal). DEX co-infusion inhibits the morphine-challenge induced EAA increase and prevents the loss of morphine's antinociceptive effect after long-term morphine infusion.
KW - Excitatory amino acids
KW - Glutamate transporters
KW - Microdialysis
KW - Morphine tolerance
KW - NMDA receptor
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UR - http://www.scopus.com/inward/citedby.url?scp=20444391331&partnerID=8YFLogxK
U2 - 10.1016/j.neuroscience.2005.03.015
DO - 10.1016/j.neuroscience.2005.03.015
M3 - Article
C2 - 15893883
AN - SCOPUS:20444391331
SN - 0306-4522
VL - 133
SP - 807
EP - 817
JO - Neuroscience
JF - Neuroscience
IS - 3
ER -