Characterization of the decrease of extracellular striatal dopamine induced by intrastriatal morphine administration.
The effect of intrastriatally-administered morphine on striatal dopamine (DA) release was studied in freely moving rats. Morphine (1, 10 or 100 microM) was given into the striatum by reversed microdialysis, and concentrations of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were simultaneously measured from the striatal dialysates. Intrastriatally-administered morphine significantly and dose-dependently decreased the extracellular concentration of DA, the concentrations of the acidic DA metabolites were only slightly decreased. The effect of morphine was antagonized by naltrexone (2.25 mg kg(-1), s.c.). Pretreatment with a preferential kappa-opioid receptor antagonist, MR2266 [(-)-5,9 alpha-diethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphane; 1 mg kg(-1), s.c.], had no effect on the decrease of extracellular DA evoked by intrastriatal morphine (100 microM). Intrastriatal administration of the selective micro-opioid receptor agonist [D-Ala2,MePhe4,Gly-ol5] enkephalin (DAMGO; 1 microM), significantly decreased the extracellular concentration of DA in the striatum. When the rats were given morphine repeatedly in increasing doses (10-25 mg kg(-1), s.c.) twice daily for 7 days and withdrawn for 48 h, the decrease of extracellular DA induced by morphine (100 microM) was significantly less than that seen in saline-treated controls. Our results show that besides the well-known stimulatory effect there is a local inhibitory component in the action of morphine on striatal DA release in the terminal regions of nigrostriatal DA neurones. Tolerance develops to this inhibitory effect during repeated morphine treatment. Furthermore, our results suggest that the effect of intrastriatally-administered morphine is mediated by the micro-opioid receptors.
Piepponen
T P
TP
Department of Pharmacy, University of Helsinki, Finland. petteri.piepponen@helsinki.fi
Mikkola
J A
JA
Ruotsalainen
M
M
Jonker
D
D
Ahtee
L
L
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001575:Benzomorphans / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism*; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D008845:Microinjections; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000819:agonists*
D001575:Benzomorphans; D004745:Enkephalins; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D015102:3,4-Dihydroxyphenylacetic Acid; C027247:MR 2266; D009020:Morphine; D004298:Dopamine; D006719:Homovanillic Acid