Spinal glucocorticoid receptors contribute to the development of morphine tolerance in rats.
BACKGROUND
Opioid analgesic tolerance is a pharmacologic phenomenon involving the mechanisms of cellular adaptation. Central glucocorticoid receptors (GRs) have been implicated in the cellular mechanism of neuronal plasticity that has many cellular steps in common with the mechanism of opioid tolerance. In a rat model of morphine tolerance, the authors examined the hypothesis that spinal GRs would play a significant role in the development of tolerance to the antinociceptive effect of morphine.


METHODS
In experiment 1, each group of rats received the GR antagonist RU38486 (0.5 or 1 microg), the mineralocorticoid receptor antagonist spironolactone (3 microg), or a vehicle, given intrathecally with morphine (10 microg) twice daily for 6 days. In experiment 2, four groups of rats were used, and each group received intrathecally 10 microg morphine plus 5 micromol GR antisense oligodeoxynucleotide, sense oligodeoxynucleotide, mixed-base oligodeoxynucleotide, or vehicle. Western blotting was used to examine the expression of GRs within the spinal cord dorsal horn. In experiment 3, the GR agonist dexamethasone (4 microg) was given intrathecally twice daily in combination with 10 microg morphine. For all experiments, the development of morphine antinociceptive tolerance was assessed using the tail-flick test.


RESULTS
The development of tolerance to the antinociceptive effect of morphine was substantially attenuated when the GR antagonist RU38486 (1 > 0.5 microg > vehicle) but not spironolactone was coadministered with morphine for 6 days. A single treatment with RU38486 did not affect morphine antinociception, nor did it reverse morphine tolerance on day 7. A similar reduction of morphine tolerance was observed in those rats treated with a GR antisense oligodeoxynucleotide but not a sense or mixed-base oligodeoxynucleotide. The administration of the GR antisense oligodeoxynucleotide also prevented GR up-regulation within the spinal cord dorsal horn. Moreover, the GR agonist dexamethasone facilitated the development of morphine tolerance.


CONCLUSIONS
The results indicate an important role of spinal GRs in the cellular mechanisms of morphine tolerance in rats and may have significant implications in clinical opioid therapy.
Lim
Grewo
G
Pain Research Group, MGH Pain Center, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, 15 Parkman Street, Boston, MA 02114, USA.
Wang
Shuxing
S
Zeng
Qing
Q
Sung
Backil
B
Mao
Jianren
J
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D004361:Drug Tolerance; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D009020:Morphine / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects
D000701:Analgesics, Opioid; D004343:Drug Implants; D006727:Hormone Antagonists; D016376:Oligonucleotides, Antisense; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D009020:Morphine; D003907:Dexamethasone