title: Effects of morphine and morphine withdrawal on adrenergic neurons of the rat rostral ventrolateral medulla.
abstract: In urethane anesthetized rats, iontophoretic application of morphine or alpha-methylnoradrenaline (alpha-MNE) inhibited (80-100%) the discharges of all putative adrenergic (C1) cells of the rostral ventrolateral medulla (RVLM). The effect of morphine was blocked selectively by naloxone 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 micrograms/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 reversed by naloxone (1 mg/kg, i.v.). Intravenous administration of naloxone 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 micrograms/kg). C-Fos expression induced by naltrexone-precipitated withdrawal was examined in the brainstem of freely moving morphine-dependent rats pretreated 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 increased 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 withdrawal-activated Fos-LIR cells in LC by 81%. In the RVLM this reduction 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-adrenergic receptors. This study suggests that, like noradrenergic cells of the LC, C1 adrenergic neurons of the RVLM are: (i) inhibited by both opiate and alpha 2-adrenergic receptor agonists; and (ii) activated 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 withdrawal may also contribute to the autonomic activation that characterizes this syndrome. Finally, inhibition of C1 cells by clonidine may contribute to the clinically recognized efficacy of this drug to attenuate autonomic signs of opiate withdrawal.
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville 22908, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Baraban
authors.forename: R L
authors.initials: RL
authors.lastname: Stornetta
authors.forename: P G
authors.initials: PG
authors.lastname: Guyenet
mesh_terms: D018663:Adrenergic Agents / Q000494:pharmacology*; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects*; D003000:Clonidine / Q000494:pharmacology; D007275:Injections, Intravenous; D007478:Iontophoresis; D008297:Male; D008526:Medulla Oblongata / Q000166:cytology / Q000187:drug effects*; D009020:Morphine / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009270:Naloxone / Q000009:adverse effects; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000032:analysis; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*
chemical_list: D018663:Adrenergic Agents; D016760:Proto-Oncogene Proteins c-fos; D018341:Receptors, Adrenergic, alpha-2; D009270:Naloxone; D009020:Morphine; D003000:Clonidine