EFFECTS OF MORPHINE AND MORPHINE-WITHDRAWAL ON ADRENERGIC-NEURONS OF THE RAT ROSTRAL VENTROLATERAL MEDULLA

In urethane anesthetized rats, iontophoretic application of morphine o r alpha-methylnoradrenaline (alpha-MNE) inhibited (80-100%) the discha rges of all putative adrenergic (C1) cells of the rostral ventrolatera l medulla (RVLM). The effect of morphine was blocked selectively by na loxone while that of alpha-MNE was blocked selectively by the alpha(2) -adrenergic antagonist idazoxan. Putative C1 cells were inhibited (75- 100%) by low i.v. doses of clonidine (10-15 mu g/kg. Most cells (7/10) were also inhibited by morphine i.v. (81% at 7 mg/kg). Two cells were slightly excited at doses below 2 mg/kg and inhibited at higher doses . Three cells were excited only. All effects of morphine i.v. were rev ersed by naloxone (1 mg/kg, i.v.). Intravenous administration of nalox one to morphine-dependent rats increased significantly the firing rate of all putative C1 adrenergic cells (from 5.8 +/- 0.9 spikes/s to 12. 3 +/- 1.5 spikes/s; n = 8). During withdrawal these cells could still be inhibited (80-100%) by i.v. injection of clonidine (15 mu g/kg). C- Fos expression induced by naltrexone-precipitated withdrawal was exami ned in the brainstem of freely moving morphine-dependent rats pretreat ed with clonidine or saline before injection of the opioid antagonist. The locus coeruleus (LC) of the same rats was examined for comparison . Morphine withdrawal without clonidine treatment significantly increa sed the number of Fos-like-immunoreactive (Fos-LIR) cells in the RVLM and LC. Clonidine pretreatment (1 mg/kg, i.p.) reduced the number of w ithdrawal-activated Fos-LIR cells in LC by 81%. In the RVLM this seduc tion averaged 37% for all cell types and 48% for C1 adrenergic cells. Further, a very large proportion of RVLM neurons that expressed c-Fos during morphine withdrawal (83%) were immunoreactive for alpha(2A)-adr energic receptors. This study suggests that, like noradrenergic cells of the LC, C1 adrenergic neurons of the RVLM are: (i) inhibited by bot h opiate acid alpha(2)-adrenergic receptor agonists; and (ii) activate d during naloxone-precipitated morphine withdrawal. Since C1 cells are considered essential to sympathetic tone generation, their inhibition by morphine may contribute to the hypotensive effects of this opioid agonist in non-dependent individuals. Their excitation during opiate w ithdrawal may also contribute to the autonomic activation that charact erizes this syndrome. Finally, inhibition of C1 cells by clonidine may contribute to the clinically recognized efficacy of this drug to atte nuate autonomic signs of opiate withdrawal.