Dataset Information

Exchange factor directly activated by cAMP-PKC? signalling mediates chronic morphine-induced expression of purine P2X3 receptor in rat dorsal root ganglia.

ABSTRACT:

Background and purpose

The P2X3 receptor is a major receptor in the processing of nociceptive information in dorsal root ganglia. We investigated the role of the P2X3 receptor and the detailed mechanisms underlying chronic morphine-induced analgesic tolerance in rats.

Experimental approach

Repeated i.t. morphine treatment was used to induce anti-nociceptive tolerance. The expression of spinal P2X3 receptor, phosphorylated PKC? and exchange factor directly activated by cAMP (Epac) were evaluated. Effects of A-317491 (P2X3 antagonist), ?-V1-2 (PKC? inhibitor) and ESI-09 (Epac inhibitor) on mechanical pain thresholds and tail-flick latency after chronic morphine treatment were determined. Co-localization of P2X3 receptor with NeuNs (marker of neuron), IB4 (marker of small DRG neurons), peripherin, PKC? and Epac were performed by double immunofluorescence staining.

Key results

Chronic morphine time-dependently increased the expression of P2X3 receptor, phosphorylated PKC? and Epac in DRGs. ?-V1-2 prevented chronic morphine-induced expression of P2X3 receptor. ESI-09 decreased the phosphorylation of PKC? and up-regulated expression of Epac after chronic morphine exposure. Mechanical pain thresholds and tail-flick latency showed that A317491, ?-V1-2 and ESI-09 significantly attenuated the loss of morphine's analgesic potency. Morphine-induced P2X3 receptor expression mainly occurred in neurons staining for IB4 and peripherin. Co-localization of P2X3 receptor with PKC? and Epac was demonstrated in the same neurons.

Conclusions and implications

Chronic morphine exposure increased the expression of P2X3 receptor, and i.t. P2X3 receptor antagonists attenuated the loss of morphine's analgesic effect. Inhibiting Epac/PKC? signalling was shown to play a significant inhibitory role in chronic morphine-induced P2X3 receptor expression and attenuate morphine-induced tolerance.

SUBMITTER: Wang W

PROVIDER: S-EPMC5913404 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Publications

Exchange factor directly activated by cAMP-PKCε signalling mediates chronic morphine-induced expression of purine P2X3 receptor in rat dorsal root ganglia.

Wang Wenying W Ma Xiaqing X Luo Limin L Huang Min M Dong Jing J Zhang Xiaoli X Jiang Wei W Xu Tao T

British journal of pharmacology 20180406 10

<h4>Background and purpose</h4>The P2X3 receptor is a major receptor in the processing of nociceptive information in dorsal root ganglia. We investigated the role of the P2X3 receptor and the detailed mechanisms underlying chronic morphine-induced analgesic tolerance in rats.<h4>Experimental approach</h4>Repeated i.t. morphine treatment was used to induce anti-nociceptive tolerance. The expression of spinal P2X3 receptor, phosphorylated PKCε and exchange factor directly activated by cAMP (Epac) ...[more]

PMID: 29500928

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