Figure 2

Scheme illustrating opiate actions in the LC.  Opiates acutely inhibit LC neurons by increasing the conductance of a K+ channel (light cross-hatch) via coupling with subtypes of Gi and/or Go, and by decreasing a Na+-dependent inward current (dark cross-hatch) via coupling with Gi/o and the consequent inhibition of adenylyl cyclase.  Reduced levels of cAMP decrease cAMP-dependent protein kinase activity and the phosphorylation of the responsible channel or pump (or closely-associated protein).  Inhibition of the cAMP pathway also decreases phosphorylation of numerous other proteins and thereby affects many additional processes in the neuron.  In addition to reducing firing rates, for example, inhibition of the cAMP pathway decreases catecholamine synthesis via reduced phosphorylation of TH, as well as initiates alterations in gene expression via regulation of transcription factors [e.g., reduced phosphorylation of CREB (associated with reduced nuclear translocation of the protein kinase catalytic subunit); reduced expression of c-fos and other IEGs (possibly mediated via CREB--dotted line); and reduced activation and nuclear translocation of C/EBP, CCAAT-enhancer binding protein(s)].  Dashed lines indicate nuclear translocation of a protein.

Upward bold arrows summarize effects of chronic morphine in the LC.  Chronic morphine increases levels of Gia and Goa, adenylyl cyclase, cAMP-dependent protein kinase, and several phosphoproteins including TH.  These changes contribute to the altered phenotype of the drug-addicted state.  For example, the intrinsic excitability of LC neurons is increased via enhanced activity of the cAMP pathway and Na+-dependent inward current, which contributes to the tolerance, dependence, and withdrawal exhibited by these neurons.  As another example, the capacity of the neurons to synthesize catecholamines is increased via induction of TH.  This altered phenotypic state may be maintained in part by persisting changes in transcription factors (e.g., CREB, c-Fos, C/EBP).  From 40.

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published 2000