Effects of U-50,488H and U-50,488H withdrawal on catecholaminergic neuronsof the rat hypothalamus

Previous report from our laboratory showed that morphine produces a stimula tory effect of hypothalamic noradrenaline (NA) turnover concurrently with e nhanced pituitary-adrenal response after its acute injection and during wit hdrawal. In the present work we have studied the effects of acute and chron ic administration of the kappa agonist U-50,488H as well as the influence o f U-50,488H withdrawal on the activity of hypothalamic NA and dopamine (DA) neurons and on the activity of hypothalamic-pituitary-adrenal (HPA) axis. A single dose of U-50,488H (15 mg/kg i.p.) significantly increased hypothal amic NA and decreased DA turnover at the time of an enhanced corticosterone release. Rats rendered tolerant to the kappa agonist by administration of U-50,488H twice a day for 4 days showed no changes in corticosterone secret ion. Additionally, a decrease in both hypothalamic MHPG (the cerebral NA me tabolite) production and NA turnover was observed, whereas DOPAC concentrat ion and DA turnover were enhanced, which indicate the development of tolera nce towards the neuronal and endocrine actions of U-50,488H. After naloxone (3 mg/kg s.c.) administration to U-50,488H-tolerant rats, we found neither behavioural signs of physical dependence nor changes in hypothalamic catec holaminergic neurotransmission. In addition; corticosterone secretion was n ot altered in U-50,488H withdrawn rats. Present data clearly indicate that tolerance develops towards the NA turnover accelerating and DA turnover dec reasing effect of U-50,488H. Importantly and by contrast to mu agonists, pr esent results demonstrate that U-50,488H withdrawal produce no changes in h ypothalamic catecholamines turnover or in corticosterone release (an index of the hypothalamus-pituitary-adrenal activity) which indicate the absence of neuroendocrine dependence on the kappa agonist. As has been proposed, th is would suggest that the mu and the kappa receptor be regulated through di fferent cellular mechanisms, as kappa agonists have a lower proclivity to i nduce dependence.