Inhibition of ß-ARK1 Ameliorates Morphine-induced Tolerance and Hyperalgesia Via Modulating the Activity of Spinal NMDA Receptors.

Authors: Zhang, Xue  Chen, Shaorui  Chen, Hong  Pan, Huilin  Zhao, Yilin 
Citation: Zhang X, etal., Mol Neurobiol. 2017 Oct 3. pii: 10.1007/s12035-017-0780-3. doi: 10.1007/s12035-017-0780-3.
Pubmed: (View Article at PubMed) PMID:28975565
DOI: Full-text: DOI:10.1007/s12035-017-0780-3

Our previous study has proposed that increased presynaptic NMDARs activities play pivotal roles in the development of opioid tolerance and hyperalgesia, and blocking spinal NMDARs attenuates chronic morphine-induced synaptic plasticity and behavior. However, the cellular signaling mechanisms remain to be investigated. The aim of this research was to address the role of ß-ARK1 in opioid analgesia. Opioid tolerance and hyperalgesia was induced by daily systemic morphine injections in rats for eight consecutive days. Whole-cell voltage-clamp was employed to record spontaneous EPSCs and evoked-AMPA-EPSCs in dorsal lamina II neurons. Strikingly, brief application of 1 µM morphine decreased the percentage of inhibition and was followed by a large LTP in the amplitude of monosynaptic evoked-AMPA-EPSCs in opioid-tolerant rats. There was no effect on these responses by postsynaptic dialysis of the G-protein inhibitor. Incubation with the NMDAR blocker AP5 potentiated morphine-induced inhibition and attenuated washout potentiation after cessation of morphine in the amplitude of AMPA-EPSCs. Incubation with ß-ARK1 inhibitor had the same effect on these responses. Incubation with ß-ARK1 inhibitor diminished NMDAR hyperfunction-increased glutamatergic synaptic transmission and enhanced the analgesic effect of morphine. Intrathecal injections of ß-ARK1 inhibitor significantly attenuated opioid-induced hyperalgesia and tolerance. ß-ARK1 plays a pivotal role in the development and maintenance of opioid tolerance and hyperalgesia. Blockade of ß-ARK1 activation ameliorates morphine tolerance and hyperalgesia via regulating the activity of spinal NMDARs. These findings provide electrophysiological evidence and useful insights regarding the mechanistic action of ß-ARK1 inhibitor as a potential anti-hyperalgesic agent to improve the efficacy of opioid therapies.


Gene Ontology Annotations
Objects Annotated

Additional Information

CRRD Object Information
CRRD ID: 13506836
Created: 2018-02-20
Species: All species
Last Modified: 2018-02-20
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.