Possible involvement of the locus coeruleus in inhibition by prostanoid EP 3 receptor-selective agonists of morphine withdrawal syndrome in rats

Abstract

We examined the mechanism of the inhibitory effect of prostanoid EP 3 receptor agonists on naloxone-precipitated withdrawal syndrome in morphine-dependent rats. Rats were rendered morphine dependent by subcutaneous (s.c.) implantation of two pellets containing 75 mg morphine for 5 days. Morphine withdrawal syndrome was precipitated by i.p. injection of naloxone (3 mg/kg). Intracerebroventricular (i.c.v.) administration of (±)-15α-hydroxy-9-oxo-16-phenoxy-17,18,19,20-tetranorprost-13- trans-enoic acid (M&B28,767: prostanoid EP 3 receptor agonist) or sulprostone (prostanoid EP 1/EP 3 receptor agonist) significantly suppressed many withdrawal signs. Northern blotting and in situ hybridization studies revealed that i.c.v. administration of M&B28,767 (1 pg/rat) attenuated the elevation of c- fos mRNA during naloxone-precipitated withdrawal in many brain regions, including the cerebral cortex, thalamus, hypothalamus and locus coeruleus. Double in situ hybridization analysis revealed that in the locus coeruleus most of the tyrosine hydroxylase mRNA-positive neurons expressed μ-opioid receptor mRNA and more than half of these neurons were positive for prostanoid EP 3 receptor mRNA. These results indicate that the suppression by prostanoid EP 3 receptor agonists of naloxone-precipitated morphine withdrawal syndrome can be attributed to the inhibition of neuronal activity in several brain regions, including the locus coeruleus, the largest source of central noradrenergic neurons.