Endomorphins 1 and 2 induce amnesia via selective modulation of dopamine receptors in mice
ABSTRACT The involvement of dopamine receptors in the amnesic effects of the endogenous micro-opioid receptor agonists endomorphins 1 and 2 was investigated by observing step-down type passive avoidance learning in mice. Although the dopamine D1 receptor agonist R(+)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol hydrochloride (R(+)-SKF38393) (0.05 and 0.1 mg/kg), the dopamine D1 receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (R(+)-SCH23390) (2.5 and 5 microg/kg) or the dopamine D2 receptor agonist N-n-phenethyl-N-propylethyl-p-(3-hydroxyphenyl)-ethylamine (RU24213) (0.3 and 1 mg/kg) had no significant effects on the endomorphin-1 (10 microg)- or endomorphin-2 (10 microg)-induced decrease in step-down latency of passive avoidance learning, (-)-sulpiride (10 mg/kg), a dopamine D2 receptor antagonist, significantly reversed the decrease in step-down latency evoked by endomorphin-2 (10 microg), but not by endomorphin-1 (10 microg). Taken together, it is likely that stimulation of dopamine D2 receptors results in the endomorphin-2-but not endomorphin-1-induced impairment of passive avoidance learning.
SourceAvailable from: Abolfazl Ardjmand[Show abstract] [Hide abstract]
ABSTRACT: The amnesic effect of morphine is well known in the laboratory animals. But, it is unclear that morphine at what times can exactly affect different phases of memory, including acquisition, consolidation, and retrieval. Therefore, we investigated the time profile of morphine's amnesic effect on passive (inhibitory) avoidance learning and memory in male Wistar rats. In order to evaluate the outcomes of pre- and post-training administrations of morphine, the animals were trained in a step-through type of passive avoidance task at various time points, and were tested 24 h after training to measure memory retrieval. The results showed that acquisition of memory was impaired in the animals that received a dose of 7.5 mg/kg of morphine (Intraperitoneally) at 0, 30 min, and 1 h before training, as evidenced by a decrease in step-through latency on the test day. Post-training administrations of morphine at 30 min and 1h, 4h except for the time immediately after training, did not impair memory consolidation. The results also showed that pre-test administrations of morphine at 0 and 30 min before the test, impaired retrieval of inhibitory avoidance memory. Taken together, the results suggest that morphine, when injected at different time points before training, after training, or before testing affects different phases of inhibitory avoidance memory. With regard to the time of injections related to each phase, other experiments can be designed to investigate molecular mechanisms involved in the impairing effect of morphine in each phase.Archives of Iranian medicine 01/2013; 16(1):34-7. · 1.11 Impact Factor
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ABSTRACT: In our efforts to develop new candidate drugs with antinociceptive and/or antidepressant-like activity, two novel endomorphin-2 (EM-2, Tyr-Pro-Phe-Phe-NH2) analogs, containing proline surrogates in position 2 were synthesized using commercially available racemic trans-4-phenylpyrrolidine-3-carboxylic acid (4-Ph-beta-Pro). The obtained mixture of two diastereoisomeric peptides (2a and 2b) was separated by HPLC and both enantiopure analogs were used in the in vitro and in vivo studies. To assign the absolute configuration to the 4-Ph-beta-Pro residues in both peptides, the stereoselective synthesis of (3R,4S)-4-phenylpyrrolidine-3-carboxylic acid was performed and this enantiomer was introduced into position 2 of EM-2 sequence. Based on the HPLC retention times we were able to assign the absolute configuration of 4-Ph-beta-Pro residues in both peptide analogs. Analog 2a incorporating (3R,4S)-4-Ph-beta-Pro residue produced strong analgesia in mice after intracerebroventricular (icv) administration which was antagonized by the mu-opioid receptor (MOR) antagonist, beta-funaltrexamine (beta-FNA). This analog also influenced an emotion-related behavior of mice, decreasing immobility time in the forced swimming and tail suspension tests, without affecting locomotor activity. The antidepressant-like effect was reversed by the delta-selective antagonist, naltrindole (NLT) and kappa-selective nor-binaltorphimine (nor-BNI). Thus, the experiments with selective opioid receptor antagonists revealed that analgesic action of analog 2a was mediated through the MOR, while the delta- and kappa-receptors (DOR and KOR, respectively) were engaged in the antidepressant-like activity. Analog 2b with (3S,4R)-4-Ph-beta-Pro in position 2 showed no antinociceptive or antidepressant-like activity in animal studies.Bioorganic & Medicinal Chemistry 09/2014; 22(17). DOI:10.1016/j.bmc.2014.06.056 · 2.95 Impact Factor
Bioscience Biotechnology and Biochemistry 01/2003; 67(11):2501-2504. DOI:10.1271/bbb.67.2501 · 1.21 Impact Factor