Endomorphins: Promising Endogenous Opioid Peptides for the Development of Novel Analgesics

Abstract

Endomorphin-1 (EM1) and endomorphin-2 (EM2) are two endogenous ligands that belong to the opioid peptide family and have the highest affinity and selectivity for the μ-opioid receptor (MOR). The neuroanatomical distribution, ultrastructural features and neural circuitry of EM-containing neuronal structures have been morphologically demonstrated. In addition, the modulation effects of the EMs in different areas reflect their potential endogenous roles in many major physiological processes, including their remarkable roles in the transmission and modulation of noxious information. The distinguished antinociceptive property of the EMs in acute and chronic pain, including neuropathic pain, cancer pain and inflammatory pain, has been revealed and investigated for therapeutic purposes. However, EMs exert adverse effects in the gastrointestinal, urinary, cardiovascular, and respiratory systems, which impede the development of EMs as new analgesics. Numerous studies have synthesized and investigated EM analogues and demonstrated that these EM derivatives had improved pharmacological properties, supporting their therapeutic perspectives. In the present review, the results of previous studies, particularly morphological and pharmacological studies, were summarized. Finally, EM modifications and their potential clinical implications were described. Applying this knowledge about EMs may provide information for further investigations in clinical application.

Paeoniflorin Attenuates Inflammatory Pain by Inhibiting Microglial Activation and Akt-NF-κB Signaling in the Central Nervous System

“…Pain is an unpleasant sensory experience induced by noxious stimuli, characterized by a heightened responsiveness to several stimuli (hyperalgesia or allodynia) [1,2]. Nearly a third of the world population experiences clinical pathological pain [3].…”

Endomorphin-2 Inhibits the Activity of the Spinoparabrachial Projection Neuron through Presynaptic Mechanisms in the Spinal Dorsal Horn in Rats

“…Mechanical (deafferentation by dorsal rhizotomy) and chemical (exposure to the primary afferent neurotoxin capsaicin) methods of disrupting spinal primary sensory afferents were used to demonstrate that EM2-ir fibers in the SDH primarily originated from neurons in the DRG [7, 43, 44]. Moreover, some EM2-ir neurons in the bilateral nucleus tractus solitarii (NTS) project to the SDH [7, 43]. Thus, EM2-ir fibers and terminals in the SDH originate from the ipsilateral primary afferents and bilateral descending fibers from NTS.…”

Fine‐Tuning the Proteolytic Stability of Peptides with Fluorinated Amino Acids

“…In 2015, the synthesis and biological activity of fluorinated, cyclic pentapeptides based on the structure of endomorphin‐2 (EM‐2) with the general sequence Tyr/Dmt‐c[ d ‐Lys‐Phe‐Phe‐Asp]NH 2 (Dmt = 2′,6′‐dimethyltyrosine) was reported . Endomorphins have attracted much attention as useful drugs for pain relief, but their application is limited by their relatively poor receptor selectivity, rapid degradation in vivo, insufficiency in crossing the blood‐brain barrier, as well as toxic side effects . Thus, the Phe residue in either position 3 or 4 of the EM‐2 peptide was individually substituted with 4‐fluorophenylalanine (4‐F‐Phe), 2,4‐difluorophenylalanine (2,4‐F 2 ‐Phe) or 4‐trifluoromethylphenylalanine (4‐CF 3 ‐Phe) (Figure ) .…”