Pre- and postsynaptic regulation of locus coeruleus neurons after chronic morphine treatment: A study of GIRK-knockout mice

While the acute inhibitory effect of opioids on locus coeruleus (LC) neurons is mediated primarily by the activation of G protein-gated inwardly-rectifying K⁺ (GIRK) channels, the 3′-5′-cyclic adenosine monophosphate (cAMP) system has been implicated in the effects of chronic morphine exposure. Presently, the impact of chronic morphine treatment on GIRK-dependent and GIRK-independent mechanisms underlying the opioid-induced inhibition of LC neurons is unclear. Here, opioid-induced postsynaptic inhibition was studied in LC neurons from wild-type and GIRK2/GIRK3 ^-/- mice at baseline and following chronic morphine treatment. The postsynaptic inhibition of LC neurons caused by the opioid agonist [Met] ⁵ enkephalin (ME) was unaffected by chronic morphine treatment in mice of either genotype. Furthermore, chronic morphine treatment had no effect on the forskolin augmentation of the ME-induced current in wild-type LC neurons and only a minor effect on the ME-induced current in LC neurons from GIRK2/GIRK3^-/- mice. Chronic morphine treatment did, however, lead to an increased frequency of spontaneous excitatory postsynaptic currents (EPSCs) in the LC. Interestingly, while forskolin augmented the EPSC frequency similarly in untreated and morphine-treated wild-type mice, as well as untreated GIRK2/GIRK3^-/- mice, it failed to increase the frequency of EPSCs in morphine-treated GIRK2/GIRK3^-/- mice. Altogether, the findings suggest that chronic morphine treatment exerts little impact on ion channels and signaling pathways that mediate the postsynaptic inhibitory effects of opioids but does enhance excitatory neurotransmission in the mouse LC.