Neurofilament proteins and cAMP pathway in brains of μ-, δ- or κ-opioid receptor gene knock-out mice: effects of chronic morphine administration

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Opiate addiction is associated with abnormalities of neurofilament (NF) proteins and upregulation of cAMP signaling in the brain, which may modulate neuronal plasticity. This study investigated, using gene-targeted mice lacking μ-, δ- or κ-opioid receptors, the role of these receptors in modulating the basal activity and the chronic effects of morphine on both intracellular targets. In WT mice, chronic treatment (5 days) with morphine (20–100 mg/kg) resulted in decreases in the immunodensity of neurofilament (NF)-L in the cerebral cortex (14–23%). In contrast, chronic morphine did not decrease NF-L in cortices of μ-, δ-, and κ-KO mice, suggesting the involvement of the three types of opioid receptors in this effect of morphine. Also, the marked increase in phosphorylated NF-H induced by chronic morphine in WT mice (two-fold) was abolished in μ-KO mice. In cortex and/or striatum of μ-, δ- and κ-KO mice, the basal immunodensities of G αi1/2 proteins, the catalytic isoform (C α) of protein kinase A (PKA) and the total content of cAMP response element-binding protein (CREB, the nuclear target of PKA) were not different from those of WT mice. In contrast, phosphorylated CREB (the active form of this transcription factor) was reduced in cortex and/or striatum (23–26%) of μ- and δ-KO mice, but not in κ-KO animals. These results suggest that the endogenous opioid tone acting on μ-/ δ-receptors tonically stimulate CREB activation in the brain. In cortex and/or striatum of WT mice, chronic morphine did not induce upregulation of the main components of the cAMP signaling pathway. In contrast, chronic morphine treatment in μ-KO mice, but not in δ- or κ-KO, resulted in a paradoxical upregulation of G αi1/2 (12–19%), PKA (19–21%,) and phosphorylated CREB (21–73%), but not total CREB, in cortex and/or striatum. The induction of heterologous receptor adaptations in μ-KO mice may explain this paradoxical effect of morphine.