Acute administration of opioids activates MORs, leading to activation of the phospholipase A2 (PLA2) pathway and inhibition of GABA (γ-aminobutyric acid)-ergic transmission. The resulting disinhibition of pain-inhibiting neurons produces the antinociceptive effects. However, MORs are known to also mediate the unwanted effects of chronically administered opioids. Confirming previous studies, the authors showed that prolonged exposure to morphine increases the trafficking of DORs, which are normally expressed at very low levels, to the plasma membrane, such that the DOR-specific agonist deltorphin can inhibit GABA-induced inhibitory postsynaptic currents (IPSCs) in central pain pathways.
To investigate the downstream mediators of the DOR-dependent effects, the authors co-administered deltorphin and the selective PLA2 inhibitor AACOCF3 to rat brainstem slices containing the nucleus raphe magnus (NRM), an area involved in regulating analgesia. The inhibitory effect of deltorphin on GABA-induced IPSCs in chronic-morphine-exposed slices was only partially blocked by AACOCF3. Because chronic exposure to opioids was known to upregulate the cyclic AMP–protein kinase A (PKA) signalling pathway, the authors administered the PKA inhibitor H89 together with the PLA2 inhibitor, which completely abolished the effects of deltorphin. Interestingly, the response to the MOR-specific agonist DAMGO following chronic morphine exposure was also dependent on these two pathways, representing a change from exclusive PLA2-dependent signalling by MORs after acute administration of morphine.
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