Molecular pharmacological study on he roles of brain cytokines in narcotic dependence

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Intracisternal injection of interleukin-1beta was shown to suppress naloxone-precipitated with-drawal syndrome in morphine dependent mouse. This effect of interleukin-1beta was mediated by CRF and prostaglandin E2. In order to clarify the target cells for interleukin-1beta in the brain, we visualized the cells expressing type 1 and type 2 interleukin-1 receptors using an in situ hybridization technique. In morphine-dependent mouse, prostaglandin E2 suppressed the withdrawal syndrome through EP3 receptors. Prostaglandin EP3 agonists suppressed the withdrawal syndrome also in the morphine-dependent rats, and attenuated the experssion of c-fos mRNA in various brain regions including the locus ceruleus. Double in situ hybridization study revealed that most of the tyrosine hydroxylase mRNA-positive neurons in the locus ceruleus expressed mu-opioid receptor mRNA and more than half of those neurons were positive to EP3 receptor mRNA,indicating that an EP3 agonist acts on the locus ceruleus noradrenergic neurons expressing mu-opioid receptors. EP3 agonists possibly suppress the excitation of the locus ceruleus noradrenergic neurons to inhibit the morphine withdrawal syndrome precipitated by naloxone.