Disruption of Cdk5-associated phosphorylation of residue threonine-161 of the delta-opioid receptor: impaired receptor function and attenuated morphine antinociceptive tolerance.
J Neurosci
; 29(11): 3551-64, 2009 Mar 18.
Article
in En
| MEDLINE
| ID: mdl-19295160
ABSTRACT
Morphine is the most commonly used and most effective analgesic in the clinic. However, its use is limited by the tolerance. Evidence indicates that the delta-opioid receptor (DOR) is essential for morphine antinociceptive tolerance; however, their underlying mechanisms are poorly understood. Here, we show that cyclin-dependent kinase 5 (Cdk5), activated in morphine antinociceptive tolerance, directly phosphorylates DOR at Thr-161 in DRG neurons. Cdk5 was found to phosphorylate Thr-161 in the second loop of DOR, but not the corresponding residue in the mu-opioid receptor (MOR). Phosphorylation at Thr-161 is required for normal cell surface expression of DOR, and the formation of DOR-MOR heterodimers. Our studies indicated that inhibition of Cdk5 activity or overexpression of a DOR mutant lacking the Cdk5 phosphorylation site displayed relatively low cell surface expression and relatively low abilities to form heterodimers of DOR and MOR; intrathecal delivery of a construct expressing the T161A mutant of DOR attenuated morphine antinociceptive tolerance in rats, suggesting that Thr-161 phosphorylation of DOR contributed to Cdk5-mediated morphine antinociceptive tolerance. Furthermore, an engineered Tat fusion-interfering peptide corresponding to the second intracellular loop of DOR (Tat-DOR-2L), reduced the cell surface expression of DOR, disrupted the formation of DOR-MOR heterodimers, and significantly attenuated the development of morphine antinociceptive tolerance after intrathecal injection. The present study indicates that Cdk5-mediated phosphorylation of DOR at Thr-161 plays a crucial role in the development of morphine tolerance and suggests the possibility of targeting DOR phosphorylation at Thr-161 to attenuate morphine antinociceptive tolerance during pain management.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Threonine
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Pain Measurement
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Receptors, Opioid, delta
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Drug Tolerance
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Cyclin-Dependent Kinase 5
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Morphine
Type of study:
Risk_factors_studies
Limits:
Animals
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Humans
/
Male
Language:
En
Journal:
J Neurosci
Year:
2009
Document type:
Article