Alterations in Rat Accumbens Endocannabinoid and GABA Content during Fentanyl Treatment: The Role of Ghrelin

Int J Mol Sci. 2017 Nov 22;18(11):2486. doi: 10.3390/ijms18112486.

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.

Keywords: 2-arachidonoylglycerol; GABA; anandamide; endocannabinoids; fentanyl; ghrelin; microdialysis; neural reward system; nucleus accumbens shell; ventral tegmental area.

MeSH terms

  • Animals
  • Behavior, Animal
  • Endocannabinoids / metabolism*
  • Extracellular Space / metabolism
  • Fentanyl / pharmacology*
  • Ghrelin / pharmacology
  • Glycine / analogs & derivatives
  • Glycine / pharmacology
  • Male
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / metabolism*
  • Rats
  • Receptors, Ghrelin / metabolism
  • Triazoles / pharmacology
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Endocannabinoids
  • Ghrelin
  • N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide
  • Receptors, Ghrelin
  • Triazoles
  • gamma-Aminobutyric Acid
  • Glycine
  • Fentanyl