Table 4:
Alterations in the level of endocannabinoids and their metabolic enzymes following opioid chronic exposure.
| Source | Species | Opioid Compound (Route) |
Addiction Model/Exposure Details |
Endocannabinoid outcome measures and method |
Results |
|---|---|---|---|---|---|
| Gonzalez et al., 2003 [59] | Male Rats | Morphine (SQ) | Non-cue-conditioned model. Escalating dose every day for 6 days Day 1: 10 and 10 mg/kg weight; day 2: 20 and 20 mg/kg; day 3: 40 and 40 mg/kg; day 4: 60 and 60 mg/kg; day 5: 80 and 80 mg/kg; and day 6: 100 mg/kg. Animals were sacrificed two hours after the last injection |
AEA level (GC/MS) | AEA level |
| → Cerebral Cortex, Striatum, Limbic forebrain, Hippocampus, Midbrain, Diencephalon, Cerebellum, Brain stem | |||||
| Vigano et.al, 2003 [54] | Male Rats | Morphine (SQ) | Non-cue-conditioned model. Stable 5mg/kg dose, twice daily for 4.5 days Animals were sacrificed two hours after the last injection |
AEA and 2-AG levels (GC/MS) | AEA level |
| → Striatum, Cortex, Hippocampus, Limbic area1, Hypothalamus, Cerebellum, Mesencephalon. | |||||
| 2-AG level | |||||
| ↓ Striatum, Cortex, Hippocampus, Limbic area1, Hypothalamus. → Cerebellum, Mesencephalon. | |||||
| Vigano et.al., 2004 [56] | Male Rats | Morphine (SQ) | Non-cue-conditioned model. Chronic morphine phase: escalating dose for 3 days (10, 20, 40 mg/kg) twice daily, Withdrawal phase: 2 weeks without drug, Expression phase: a single dose of 5mg/kg morphine after withdrawal Animals were sacrificed 30 minutes after the last injection or after the withdrawal phase |
AEA and 2-AG levels (LC-APCI-MS) FAAH activity (in vitro arachidonoyl-[14C]ethanolamide metabolism) | AEA level |
| ↑ In NAc, PFC, CP, and Hippocampus at the end of withdrawal and reinstatement phases → In NAc, PFC, CP, and Hippocampus at the end of the chronic morphine phase | |||||
| 2-AG level | |||||
| ↓ in NAc at the end of the chronic morphine phase. In NAc, CP and hippocampus at the end of withdrawal and expression phases → in CP and hippocampus after chronic phase. In PFC after chronic morphine, withdrawal, and reinstatement phases. | |||||
| FAAH activity | |||||
| ↓ in CP and hippocampus at the end of the chronic phase and reinstatement phases. | |||||
|
Note: The above-mentioned significant changes at the end of the reinstatement phase were compared to saline control rats. However, there are some significant changes in the morphine-treated animal at the end of the withdrawal phase and after receiving the expression dose. ↓ AEA level in CP and Hippocampus → AEA level in NAc and PFC ↑ 2-AG in the Hippocampus → 2-AG in the CP, NAc and PFC | |||||
| Caille´ et.al., 2007 [71] | Male Rats | Heroin (IV) | SA model. After the rats acquired a stable SA behavior, a 2-hour session in the SA chamber alongside In vivo micro-dialysis sampling was started. |
AEA and 2-AG levels (LC/MS) | AEA level |
| ↑ in NAc shell (directly correlated with heroin dose) during the self-administration session vs. before the session. → in NAc shell before self-administration session vs. controls | |||||
| Mean self-administered heroin during the 2-hour sampling session administration: 443 ± 61 μg/kg | 2-AG level | ||||
| ↓ in NAc shell (Inversely correlated with heroin dose) during the self-administration session vs. before the session. → in NAc shell before self-administration session vs. controls | |||||
| Li et.al, 2017 [67] | Male Rats | Morphine SQ) | CPP model. Conditioning phase: Escalating daily dose for 4 days (5, 8, 10, and 15 mg/kg) with (morphine-paired group) and without (morphine-unpaired group) place conditioning procedure. Extinction phase: five days without morphine. Reinstatement phase: Single 5 mg/Kg morphine injection. The control group received saline injections throughout the investigation except for the reinstatement phase, in which they also received the morphine injection. Animals were sacrificed 24 hours after each phase |
NAPE-PLD, DAGLα/β, FAAH, and MAGL mRNA expression (RT-PCR) | NAPE-PLD expression |
| → in the dorsal hippocampus after conditioning, extinction, and reinstatement phases. | |||||
| DAGLα/β expression | |||||
| → in the dorsal hippocampus after conditioning, extinction, and reinstatement phases. | |||||
| FAAH expression | |||||
| ↑ in dorsal hippocampus after conditioning phase. → in the dorsal hippocampus after extinction and reinstatement phases. | |||||
| MAGL expression | |||||
| ↑ in dorsal hippocampus after conditioning phase. ↓ in the dorsal hippocampus after the reinstatement phase. → in the dorsal hippocampus after the extinction phase. | |||||
| Note: significant changes were observed only in the morphine-paired group but not in the morphine-unpaired group. The comparisons in the conditioning and extinction phases are between morphine-treated and saline-treated rats. However, in the reinstatement phase, the comparison is between morphine-pretreated and saline-pretreated rats that both received a morphine injection. | |||||
| Zhang et al., 2021 [57] | Male Rats | Morphine (IP) | Non-cue-conditioned model. Stable dose of 5 mg/kg, twice daily for 5 days. Animals were sacrificed one hour after the last injection. |
FAAH and NAPE-PLD Protein expression (proteome analysis) MAGL and DAGLα protein expression (proteome analysis and Western blot) |
FAAH expression |
| → VTA | |||||
| NAPE-PLD expression | |||||
| → VTA | |||||
| MAGL expression | |||||
| → VTA | |||||
| DAGLα expression | |||||
| → VTA | |||||
| Non-cue-conditioned model. Stable dose of 5 mg/kg, twice daily for 5 days, then an additional 5 mg/kg on the next day (challenge injection) and measuring endocannabinoid trends. In vivo, micro-dialysis samples were obtained every 30 minutes until 6 hours after the challenge injection. |
AEA and 2-AG levels (Mass spectrometry) | AEA level | |||
| → In VTA before challenge injection vs. saline-treated control group. In VTA before vs. after challenge injection. | |||||
| 2-AG level | |||||
| → In VTA before challenge injection vs. saline-treated control group. In VTA before vs. after challenge injection |
Abbreviations: AEA: Anandamide; DAGLα: diacylglycerol lipase α; CP: Caudate-putamen; FAAH: Fatty acid amide hydrolase; GC/MS: Gas chromatography, mass spectrometry; IP: Intra-peritoneal; IV: Intra-venous; MAGL: Monoacylglycerol lipase; NAc: Nucleus accumbens; NAPE-PLD: N-Acyl-Phosphatidylethanolamine-Hydrolyzing Phospholipase D; RT-PCR: Reverse transcriptase polymerase chain reaction; SA: Self-administration; PFC: Pre-frontal cortex; VTA: Ventral tegmental area; 2-AG: 2-Arachidonoylglycerol. Definitions: ↑: Increased significantly; ↓: Decreased significantly; →: Not changed/insignificant change.
1
Authors specimen of the limbic area contained nucleus accumbens, septum nuclei, and parts of the anterior amygdaloid nuclei.