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

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 β-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 β-ARK1 inhibitor had the same effect on these responses. Incubation with β-ARK1 inhibitor diminished NMDAR hyperfunction-increased glutamatergic synaptic transmission and enhanced the analgesic effect of morphine. Intrathecal injections of β-ARK1 inhibitor significantly attenuated opioid-induced hyperalgesia and tolerance. β-ARK1 plays a pivotal role in the development and maintenance of opioid tolerance and hyperalgesia. Blockade of β-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 β-ARK1 inhibitor as a potential anti-hyperalgesic agent to improve the efficacy of opioid therapies.

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