Novel chimeric peptides of endomorphin-2 and the active fragments of ghrelin exhibit blood-brain barrier permeability and central antinociceptive effects with reduced opioid-related side effects.

Pharmacological research has showed that multi-targeted drug therapies offer superior efficacy and reduced side effects compared to single-target drug therapies. In this study, we designed and characterized four novel chimeric peptides G (1-5)-EM2, EM2-G (1-5), G (1-9)-EM2 and EM2-G (1-9) which incorporate endomorphin-2 (EM-2) and the active fragments of ghrelin. Calcium mobilization assays revealed that these four chimeric peptides acted as weak mixed agonists for the μ-opioid receptor (MOR), κ-opioid receptor (KOR), and growth hormone secretagogue receptor 1α (GHS-R1α). The results of fluorescence imaging experiments indicated that G (1-5)-EM2 and G (1-9)-EM2 could penetrate the blood-brain barrier (BBB) following intravenous (i.v.) injection. All chimeric peptides induced almost equal antinociceptive effects compared with EM-2 or better antinociceptive effects than EM-2 after intracerebroventricular (i.c.v.) injection in the acute pain in mice. Among them, G (1-5)-EM2 could cross the BBB and enter the brain to induce antinociceptive effect through central opioid receptors after i. v. Injection. Our findings demonstrated that the chimeric peptides produced significant antinociception mainly via MOR, DOR and GHS-R1α without inducing antinociceptive tolerance, or with a lower tendency for antinociceptive tolerance after i. c.v. Injection in the acute pain in mice. Furthermore, the chimeric peptides mitigated or eliminated the digestive side effects associated with EM-2. The collective results highlight G (1-5)-EM2 as the most promising candidate among the chimeric peptides. The chimeric peptides represent a promising class of potential analgesics for clinical pain management. However, further optimization is necessary to maximize their therapeutic potential.