A Novel Multitarget Mu- and Delta-Opioid Receptors Agonist HAGD Has Peripherally Restrictive Potent Analgesia with Less Side Effects in Mice and Minimal Impact on Human Sperm Motility

Abstract ObjectivePain is a common clinical symptom. Although a variety of opioid analgesics have been developed, the side effects including negative impact on human sperm motility still hinder their application. Aim of this study is to develop a novel opioid analgesic, a multitarget peptide HAGD (H-Tyr-D-AIa-GIy-Phe-NH2) which has less side effects and minimal impact on sperm motility.MethodsThe peripheral antinociceptive effects of HAGD were appraised in a series of preclinical mice pain models, including the tail-flick test, carrageenan-induced inflammatory pain, acetic acid-induced writhing test and formalin test. In conditioned place preference experiment, open field test, gastrointestinal transit test and rotarod test, the side effects of HAGD in mice were assessed. The impacts of HAGD on sperm motility in vitro were investigated.ResultsHAGD produced equipotent antinociception compared with morphine. HAGD was stronger in terms of analgesia intensity in chemical stimulation pain of formalin test phase I. The antinociception was mediated by mu- and delta-opioid receptors. HAGD didn’t induce conditioned place preference and hyperlocomotion, but morphine did. Both HAGD and morphine had no impacts on motor coordination. HAGD had a limited side effect in gastrointestinal transit, while morphine inhibited gastrointestinal transit to a greater extent. However, HAGD had minimal impact on human sperm motility, whereas morphine declined sperm motility at concentrations of 1 × 10-7 mol/l and 1 × 10-8 mol/l at 3.5 h of incubation.Conclusion HAGD may be a better candidate for future development of novel multitarget opioid analgesics with less side effects and minimal impact on human sperm motility.