Effect of chronic prenatal morphine treatment of mu-opioid receptor-regulated adenylate cyclase activity and neurotransmitter release in rat brain slices.
Timed-pregnant rats received a semisynthetic diet with or without morphine (0.5-1 mg/g) for 2 weeks. After 21 days of gestation the morphine-dependent dams were decapitated and the foetal brains were dissected. Chronic morphine administration caused a profound increase of adenylate cyclase activity stimulated by postsynaptic D1 dopamine receptors in striatal slices. The relative inhibitory effect of [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAGO) on D1-stimulated cyclic AMP (cAMP) production was unaffected. In contrast, cAMP production induced via direct activation of the catalytic unit of adenylate cyclase with forskolin was not changed upon long-term morphine treatment, although DAGO strongly inhibited the effect of forskolin. The electrically evoked release of [3H]noradrenaline (NA) from superfused neocortical slices was strongly enhanced upon morphine treatment, whereas release induced by the calcium ionophore A23187, bypassing voltage-sensitive calcium channels, was unchanged. Again, the inhibitory effect of the mu receptor agonist DAGO was unaffected in neocortical slices from morphine-treated rats. It is suggested that tolerance to morphine may be caused by the fact that the opiate is acting against up-regulated signal transduction mechanisms, rather than by desensitization of central mu-opioid receptors. The pre- and postsynaptic changes may include an enhanced expression and/or biochemical modification of D1 receptors, Gs proteins and calcium channels in central neurons on which mu-opioid receptors are present. At the same time, these adaptive changes may underlie morphine withdrawal phenomena.
Department of Pharmacology, Medical Faculty, Free University, Amsterdam, The Netherlands.
T J
TJ
De Vries
B J
BJ
Van Vliet
F
F
Hogenboom
G
G
Wardeh
J W
JW
Van der Laan
A H
AH
Mulder
A N
AN
Schoffelmeer
D000222:Adaptation, Physiological; D000262:Adenylyl Cyclases / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000196:embryology / Q000201:enzymology; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000502:physiology; D009020:Morphine / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology*; D017450:Receptors, Opioid, mu; D009435:Synaptic Transmission / Q000187:drug effects
D018377:Neurotransmitter Agents; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D009020:Morphine; D000262:Adenylyl Cyclases; D009638:Norepinephrine