Effects of U‐50,488H and U‐50,488H withdrawal on c‐ fos expression in the rat paraventricular nucleus. Correlation with c‐ fos in brainstem catecholaminergic neurons

In the present work, we have studied the expression of Fos during acute and chronic administration of the κ ‐opioid receptor agonist U‐50,488H and after U‐50,88H withdrawal in the rat hypothalamic paraventricular nucleus (PVN). Fos production was also studied in brainstem regions that innervate the PVN: the A 2 cell group of the nucleus of solitary tract (NTS‐A 2 ) and the A 1 cell group of the ventrolateral medulla (VLM‐A 1 ), combined with immunostaining for tyrosine hydroxylase (TH) for immunohistochemical identification of active neurons after acute U‐50,488H administration. For acute experiments, male rats were treated with saline i.p. for 4 days. On day 5, rats were given saline or U‐50,488H (15 mg kg −1 , i.p.). Other groups of rats were rendered tolerant/dependent on U‐50,488H by injecting the drug twice daily (15 mg kg −1 , i.p.) for 4 days. Control animals received saline i.p. on the same time schedule. On day 5, rats were treated with vehicle i.p., with U‐50,488H (15 mg kg −1 ) or with the selective κ opioid‐receptor antagonist nor‐binaltorphimine (Nor‐BNI, 5 mg kg −1 , i.p.). Using immunohistochemical staining of Fos, present results indicate that acute administration of U‐50,488H produced an increase in Fos expression in the PVN and in the noradrenergic A 1 and A 2 cell groups. Moreover, when double‐label immunohistochemistry was used to identify Fos and catecholaminergic‐positive neurons in the brainstem, it was found that catecholaminergic‐positive neurons in the NTS and VLM showed a significant increase in Fos expression in response to acute U‐50,488H injection. Chronic application of U‐50,488H leads to the development of tolerance towards their effects on Fos expression in the PVN as well as in the NTS and VLM. However, administration of Nor‐BNI to U‐50,488H‐dependent rats did not induce any changes in Fos immunoreactivity in the PVN or in the brainstem. These findings demonstrate that acute activation of κ ‐opioid receptors results in different altered patterns of immediate‐early gene expression in the PVN, which occurs concurrently with an increased activity of their inputs from the brainstem. Interestingly in contrast to morphine withdrawal, present results demonstrate that rats withdrawn from U‐50,488H did show no changes in Fos‐immunoreactivity in the PVN, NTS or VLM, indicating the absence of dependence on the κ ‐agonist under the present experimental conditions.British Journal of Pharmacology (2003) 138 , 1544–1552. doi: 10.1038/sj.bjp.0705179