The proenkephalin A-processing product peptide E, which encompasses two enkephalin sequences, has a much lower opioid activity than beta-endorphin

Peptide E is a 25-amino acid peptide derived from proenkephalin A that was originally isolated from the bovine adrenal medulla. Bovine peptide E (BPE) , which possesses a Met- and a Leu-enkephalin sequence at its N- and C-term inus, respectively, has been described as a highly potent and selective mu- opioid receptor agonist. Paradoxically, the frog counterpart of peptide E ( FPE), which exhibits only two amino acid substitutions (Met(15) --> Gin and Leu(25) --> Met) compared with BPE, was found to be totally devoid of anti nociceptive activity. To decipher this apparent discrepancy, we have decide d to compare the structural and pharmacological characteristics of FPE, BPE , and the chimeric peptide [Gln(15)]BPE (Q15BPE). In methanol, all three pe ptides exhibited virtually the same conformation, the central region of eac h peptide (residues 10-20) beings involved in a regular helix. Intracerebro ventricular administration of FPE, BPE, or Q15BPE, at doses up to 1000 ng p er mouse, did not induce any analgesic effects, as evaluated by the hot pla te and writhing tests, whereas, in the same tests, beta-endorphin at a dose of 100 ng provoked profound analgesia. Concomitant administration of FPE, BPE, or Q15BPE (100 ng) with the aminopeptidase-N inhibitor bestatin (50 mu g) or the endopeptidase 24-11 inhibitor thiorphan (10 mu g) did not produc e analgesic responses. Antinociceptive effects were only observed when very high doses of FPE, BPE, and Q15BPE (10000 ng per mouse) were administered. These data clearly demonstrate that, contrary to what has been previously reported, peptide E is virtually devoid of opioid activity. (C) 1999 Elsevi er Science Inc. All rights reserved.