Evidence of the preferential involvement of .mu.-receptors in analgesia using enkephalins highly selective for peripheral .mu. or .delta. receptors

Abstract

In order to study the preferential involvement of mu or delta receptors in the analgesic effects of enkephalins, several peptides which selectively interact with these two kinds of receptors in peripheral organs were synthesized. The inhibitory potency on the electrically stimulated mouse vas deferens (delta receptors) of the short peptide Tyr-D-Ala-Gly-NH-CH(CH3)CH2CH(CH3)2 (6) is 2100 times lower (IC50 = 1220 nM) than that of the longer and more hydrophilic peptide Tyr-D-Ser-Gly-Phe-Leu-Thr (10) (IC50 = 0.58 nM). In contrast, the IC50 values of all the synthesized compounds on the guinea pig ileum assay (mu receptors) are in the same range (100-360 nM). Likewise, their analgesic activities in mice, measured on the hot-plate test after intracerebroventricular injection, are similar. Therefore, the dissociation between antinociceptive properties in mice and potencies on the mouse vas deferens unambiguously reflects a preferential implication of mu receptors in analgesia. The possible involvement of brain delta receptors in behavioral effects is discussed.

Use of preproenkephalin knockout mice and selective inhibitors of enkephalinases to investigate the role of enkephalins in various behaviours

“…Previous studies have demonstrated a predominant involvement of mu opioid receptors in endogenous opioid-induced analgesia, at least with respect to thermal nociceptive stimuli (Dauge et al 1987;Fang et al 1986;Gacel et al 1981;Matthes et al 1996;Noble et al 1992). It has been shown that, probably for conformational reasons, other opioid peptides, such as β-endorphin and/ or endomorphins, which have a great affinity for mu receptors, appear to be resistant to NEP, but to a lesser extent to APN (Champion et al 1997;Turner et al 1987).…”

Peptides

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Synthesis and binding properties to DNA and to opioid receptors of enkephalin‐ellipticinium conjugates

“…Boc-Tyr-D-Ala-Gly 1 and Boc-Tyr-D-Ala-Gly-Phe-D-Leu 5 were prepared as previously described (8,16). in anhydrous THF (30mL), cooled in an ice water bath, were successively added a solution of 3-bromopropylamine, hydrobromide (536 mg, 2.45 mmol) and triethylamine (0.035mL) in CHCl, (30mL), a solution of HOBT (377 mg, 2.45 mmol) in anhydrous T H F (lOmL), and a solution of DCC (503 mg, 2.45 mmol) in CHCl, (10 mL).…”