Ghrelin and endocannabinoids participation in morphine-induced effects in the rat nucleus accumbens.
OBJECTIVE
In addition to dopamine, endocannabinoids are thought to participate in neural reward mechanisms of opioids. Number of recent studies suggests crucial involvement of ghrelin in some addictive drugs effects. Our previous results showed that ghrelin participates in morphine-induced changes in the mesolimbic dopaminergic system associated with reward processing. The goal of the present study was to test whether the growth hormone secretagogue receptor (GHS-R1A) antagonist JMV2959 was able to influence morphine-induced effects on anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG) in the nucleus accumbens shell (NACSh).


METHODS
We used in vivo microdialysis to determine changes in levels of AEA and 2-AG in the NACSh in rats following (i) an acute morphine dose (5, 10 mg/kg s.c.) with and without JMV2959 pretreatment (3, 6 mg/kg i.p.) or (ii) a morphine challenge dose (5 mg/kg s.c.) with and without JMV2959 (3, 6 mg/kg i.p.) pretreatment, administered during abstinence following repeated doses of morphine (5 days, 10-40 mg/kg). Co-administration of ghrelin (40 ug/kg i.p.) was used to verify the ghrelin mechanisms involvement.


RESULTS
Pretreatment with JMV2959 significantly and dose-dependently reversed morphine-induced anandamide increases in the NACSh in both the acute and longer-term models, resulting in a significant AEA decrease. JMV2959 significantly intensified acute morphine-induced decreases in accumbens 2-AG levels and attenuated morphine challenge-induced 2-AG decreases. JMV2959 pretreatment significantly reduced concurrent morphine challenge-induced behavioral sensitization. JMV2959 pretreatment effects were abolished by co-administration of ghrelin.


CONCLUSIONS
Our results indicate significant involvement of ghrelin signaling in morphine-induced endocannabinoid changes in the NACSh.
Department of Pharmacology, Third Faculty of Medicine, Charles University, Ruska 87, Prague 10, 100 34, Czech Republic. magdalena.sustkova@lf3.cuni.cz.
Magdalena
M
Sustkova-Fiserova
Department of Pharmacology, Third Faculty of Medicine, Charles University, Ruska 87, Prague 10, 100 34, Czech Republic.
Pavel
P
Jerabek
Department of Pharmacology, Third Faculty of Medicine, Charles University, Ruska 87, Prague 10, 100 34, Czech Republic.
Tereza
T
Havlickova
Department of Organic Technology ICT, Laboratory of Medicinal Diagnostics, Technicka 5, Prague 6, 166 28, Czech Republic.
Kamila
K
Syslova
Department of Organic Technology ICT, Laboratory of Medicinal Diagnostics, Technicka 5, Prague 6, 166 28, Czech Republic.
Petr
P
Kacer
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids / Q000378:metabolism / Q000502:physiology*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D054439:Ghrelin / Q000502:physiology*; D005989:Glycerides / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors; D011986:Receptors, Somatotropin / Q000037:antagonists & inhibitors; D013239:Stereotyped Behavior / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology
D001095:Arachidonic Acids; D063388:Endocannabinoids; D054439:Ghrelin; D005989:Glycerides; C569751:N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide; D009294:Narcotics; D053284:Polyunsaturated Alkamides; D054440:Receptors, Ghrelin; D011986:Receptors, Somatotropin; D014230:Triazoles; D009020:Morphine; C094503:glyceryl 2-arachidonate; D005998:Glycine; C078814:anandamide
2-Arachidonoylglycerol; Acute; Anandamide; Challenge during abstinence; Endocannabinoids; Ghrelin; Microdialysis; Morphine; Neural reward system; Nucleus accumbens shell; Stereotyped behavior