Met-Enkephalin-Arg-Phe

Angiotensin-converting enzyme (ACE) regulates blood pressure by cleaving angiotensin I to produce angiotensin II. In the brain, ACE is especially abundant in striatal tissue, but the function of ACE in striatal circuits remains poorly understood. We found that ACE degrades an unconventional enkephalin heptapeptide, Met-enkephalin-Arg-Phe, in the nucleus accumbens of mice. ACE inhibition enhanced µ-opioid receptor activation by Met-enkephalin-Arg-Phe, causing a cell type-specific long-term depression of glutamate release onto medium spiny projection neurons expressing the Drd1 dopamine receptor. Systemic ACE inhibition was not intrinsically rewarding, but it led to a decrease in conditioned place preference caused by fentanyl administration and an enhancement of reciprocal social interaction. Our results raise the enticing prospect that central ACE inhibition can boost endogenous opioid signaling for clinical benefit while mitigating the risk of addiction.

Acid extracts of the brain of the pacific hagfish, Eptatretus stouti, and the marine lamprey, Petromyzon marinus, were each fractionated by gel filtration chromatography and aliquots of column fractions were screened with radioimmunoassays (RIAs) specific for pro-dynorphin-related end products and for pro-enkephalin-related end products. Only pro-enkephalin-related immunoreactive forms were detected. The enkephalin-sized immunoreactive material, isolated for each species, was separately fractionated by reverse-phase high-performance liquid chromatography (HPLC). Aliquots of column fractions were screened with RIAs specific for Met-enkephalin, Leu-enkephalin, Met-enkephalin-Arg-Phe, and Met-enkephalin-Arg-Gly-Leu. In the hagfish brain, immunoreactive forms with the same retention times as synthetic Met-enkephalin and Leu-enkephalin were detected in a ratio of approximately 2:1. In addition, an immunoreactive form was detected with the Met-enkephalin-Arg-Phe-specific RIA. This form had the same chromatographic properties as synthetic Met-enkephalin-Arg-Phe. Analyses with the Met-enkephalin-Arg-Gly-Leu RIA were negative. HPLC analysis of the lamprey enkephalin-related material revealed the presence of authentic Met-enkaphalin and Leu-enkephalin in a molar ratio of 3:1. C-terminally extended forms of Met-enkaphalin were not detected in the lamprey extracts. Collectively these observations indicate that pro-enkephalin-related opioid peptides are present in the brain of cyclostomes.

Endogenous peptide, Met-enkephalin-Arg-Phe (Tyr-Gly-Gly-Phe-Met-Arg-Phe; MERF) induces effects like antinociception, inhibit contraction of guinea pig ileum, mouse vas deferens and anti-tussive action. However, results regarding its functional efficiency and selectivity are controversial. Therefore, present study was undertaken to investigate whether MERF on systemic (intra-peritoneal, i.p.) route of administration induce any antinociception or not; to scrutinize the effect of 6 days chronic i.p. treatment of MERF on expression of mu (MOR1), delta (DOR1) and kappa (KOR1) opioid receptors; and finally, the antinociceptive effect of two synthetic peptides, MERFamide and (D-Ala(2))-MERFamide was compared with MERF on intracerebroventricular administration in order to understand the role of FMRF moiety in analgesic effect of MERF. Pharmacological results revealed that only 68.4 and 91.2 micromol/kg dose induce significant antinociception among various doses. Further, on 6 days chronic treatment, MERF induced significant antinociception in comparison to saline. Differential expression of MOR1 and KOR1 showed continuous up-regulation throughout the treatment whereas DOR1 showed down-regulation in initial 3 days followed by subsequently up-regulation during the latter observable period. Moreover, variation in opioid receptors expression had not affected the MERF antinociception. In conclusion, present study discursively demonstrates that MERF during chronic treatment interacts with all three opioid receptors (mu, delta and kappa) in rats and differently regulates their expression. Further, the interaction was such that the induction was mainly observed at molecular/expression level and not at pharmacological level to affect antinociception.