Stimulation of mitogen-activated protein kinase kinases (MEK1/2) by μ-, δ- and κ-opioid receptor agonists in the rat brain:: Regulation by chronic morphine and opioid withdrawal

Opioid addiction modulates the extracellular signal-regulated kinase (ERK) leading to synaptic plasticity in the brain. ERK1/2 are stimulated by mitogen-activated protein kinase kinases (MEK1/2), but little is known about the regulation of MEK activity by opioid drugs. This study was designed to assess the acute effects of selective mu-, delta-, and kappa-opioid receptor agonists, as well as those induced by chronic morphine and opioid withdrawal, on the content of phosphorylated MEK1/2 in the rat brain. Sufentanil (1-30 mu g/kg, 30-120 min) induced dose- and time-dependent increases in MEK1/2 phosphorylation in the cerebral cortex and corpus striatum (30-177%) through a naloxone-sensitive mechanism. Morphine (100 mg/kg, 2 h) also augmented MEK1/2 phosphorylation in the both brain regions (50-70%). Similarly, the selective delta-opioid receptor agonist SNC-80 (10 mg/kg, 30 min) increased MEK1/2 activity in the cortex (60%) that was antagonized by naltrindole. In contrast, the selective K-opioid receptor agonist (-)-US0488H (10 mg/kg, 30-120 min) did not modify significantly MEK1/2 phosphorylation in the cortex. Chronic morphine (10-100 mg/kg, 5 days) was not associated with alterations in the content of phosphorylated MEK1/2 in the brain (induction of tachyphylaxis to the acute effects). In morphine-dependent rats, however, naloxone (2 mg/kg)-precipitated withdrawal (2-6 h) induced robust increases in MEK1/2 phosphorylation in cortex (27-49%) and striatum (83-123%). Spontaneous opioid withdrawal (24 h) in morphine-dependent rats did not alter MEK1/2 activity in the brain. The findings may be relevant in the context of the pivotal role played by the MEK/ERK pathway in various long-lasting forms of synaptic plasticity associated with opioid addiction. (c) 2006 Elsevier B.V. All rights reserved.