Abstract
The opioid-induced rise of extracellular dopamine, endocannabinoid anandamide and γ-aminobutyric acid (GABA) concentrations triggered by opioids in the nucleus accumbens shell (NACSh) most likely participate in opioid reward. We have previously demonstrated that systemic administration of ghrelin antagonist (JMV2959) significantly decreased morphine-induced dopamine and anandamide (N-arachidonoylethanolamine, AEA) increase in the NACSh. Fentanyl is considered as a µ-receptor-selective agonist. The aim of this study was to test whether JMV2959, a growth hormone secretagogue receptor (GHS-R1A) antagonist, can influence the fentanyl-induced effects on anandamide, 2-arachidonoylglycerol (2-AG) and GABA in the NACSh and specify the involvement of GHS-R1A located in the ventral tegmental area (VTA) and nucleus accumbens (NAC). Using in vivo microdialysis in rats, we have found that pre-treatment with JMV2959 reversed dose dependently fentanyl-induced anandamide increases in the NACSh, resulting in a significant AEA decrease and intensified fentanyl-induced decreases in accumbens 2-AG levels, with both JMV2959 effects more expressed when administered into the NACSh in comparison to the VTA. JMV2959 pre-treatment significantly decreased the fentanyl-evoked accumbens GABA efflux and reduced concurrently monitored fentanyl-induced behavioural stimulation. Our current data encourage further investigation to assess if substances affecting GABA or endocannabinoid concentrations and action, such as GHS-R1A antagonists, can be used to prevent opioid-seeking behaviour.
Highlights
Gut-brain orexigenic peptide ghrelin [1], a natural ligand of the growth hormone secretagogue receptor (GHS-R1A), has been recently shown to play a critical role in food reward [2] as well as reward, motivation and intake of alcohol and reward of several stimulants
We have shown in our earlier study [16] that premedication with the GHS-R1A antagonist, a triazole non-peptidic derivative JMV2959 [18], significantly and dose-dependently reduced morphine-induced dopamine efflux in the nucleus accumbens shell (NACSh), a brain structure that is crucially important for drug reward mediation [19,20], and attenuated behavioural stimulation, stereotypical behaviours induced by morphine
The goal of the present study was to establish whether the GHS-R1A antagonist, the substance JMV2959 could influence the fentanyl-induced effects on anandamide and 2-AG in the NACSh and specify the involvement of GHS-R1A located in the ventral tegmental area (VTA) and NAC
Summary
Gut-brain orexigenic peptide ghrelin [1], a natural ligand of the growth hormone secretagogue receptor (GHS-R1A), has been recently shown to play a critical role in food reward [2] as well as reward, motivation and intake of alcohol and reward of several stimulants (for review, see [3,4]). We have shown in our earlier study [16] that premedication with the GHS-R1A antagonist, a triazole non-peptidic derivative JMV2959 [18], significantly and dose-dependently reduced morphine-induced dopamine efflux in the nucleus accumbens shell (NACSh), a brain structure that is crucially important for drug reward mediation [19,20], and attenuated behavioural stimulation, stereotypical behaviours induced by morphine. This was subsequently confirmed in mice [15]. This suggests a significant involvement of central ghrelin system in changes induced by morphine/opioids in the mesolimbic dopaminergic system, changes which are associated with processing of neural reward
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