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Abstract: Endomorphin 1 (EM1) and endomorphin 2 (EM2) are highly potent and selective μ-opioid receptor agonists and have significant antinociceptive action. In the μ-selective pocket of endomorphins (EMs), Pro2 residue is a spacer and directs the Tyr1 and Trp3/Phe3 side chains into the required orientation. The present work was designed to substitute the peptide bond between Tyr1 and Pro2 of EMs with a reduced (CH2NH) bond and study the agonist potency and antinociception of EM1[ψ] (Tyr[ψ(CH2NH)]Pro-Trp-Phe-NH2) and EM2[ψ] (Tyr[ψ(CH2NH)]Pro-Phe-Phe-NH2). Both EM1[ψ] and EM2[ψ] are partial μ opioid receptor agonists showing significant loss of agonist potency in GPI assay. However, EMs[ψ] exhibited potent supraspinal antinociceptive action in vivo. In the mice tail-flick test, EMs[ψ] (1, 5, 10 nmol/mouse, i.c.v.) produced potent and short-lasting antinociception in a dose-dependent and naloxone (1 mg/kg) reversed manner. At the highest dose of 10 nmol, the effect of EM2[ψ] was prolonged and more significant than that of EM2. In the rat model of formalin injection induced inflammatory pain, EMs[ψ] (0.1, 1, 10 nmol/rat, i.c.v.), like EMs, exerted transient but not dose-dependent antinociception. These results suggested that in the μ-selective pocket of EMs, the rigid conformation induced by the peptide bond between Tyr1 and Pro2 is essential to regulate their agonist properties at the μ opioid receptors. However, the increased conformational flexibility induced by the reduced (CH2NH) bond made less influence on their antinociception. [Copyright &y& Elsevier]

In the present study, it was found that intraperitoneal (i.p.) pre-injection of N(G)-nitro-L-arginine methyl ester (L-NAME) significantly influenced the endomorphin-1 (EM-1) and endomorphin-2 (EM-2) induced antinociception. These effects could be inhibited or reversed by L-Arg or naloxone. Our results suggest that the modulatory effect of NO system on the mu-receptor evoked analgesia is different between the two mu receptor subtypes.

Aim: To study the effects of opioid receptor agonists endomorphin-1 and -2 on contractile responses of rat thoracic aorta rings to phenylephrine (PE) and angiotensin II (Ang II), and their possible mechanism in vitro., Methods: Isometric tension recording was progressed in thoracic aorta rings from Wistar rats., Results: Pretreatment of morphine, endomorphin-1 and -2 (0.1, 1, and 10 micromol/L) could inhibit the contractile responses of the endothelium-intact aorta rings to PE (0.1 micromol/L) and Ang II ( 1 micromol/L) in a concentration-dependent manner (P < 0.01), but could not inhibit the contraction of rings without endothelium (P > 0.05). Naloxone (1 micromol/L) could partially antagonize the effects of endomorphine-1 and -2 (P < 0.01). N(omega)-nitro-L-arginine (L-NNA, 10 micromol/L) or endothelial rubbing could completely blocked the effects of morphine, endomorphine-1 and -2 (P < 0.01)., Conclusion: Endomorphin-1 and -2 could inhibit PE- and Ang II-induced contractions of rat aorta rings, which was partially by naloxone-sensitive mechanism and related to the release of nitric oxide from vascular endothelium.