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 remar… Show more
“…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].…”
Background/Aims: Paeoniflorin (PF) is known to have anti-inflammatory and paregoric effects, but the mechanism underlying its analgesic effect remains unclear. The aim of this study was to clarify the effect of PF on Freund’s complete adjuvant (CFA)-induced inflammatory pain and explore the underlying molecular mechanism. Methods: An inflammatory pain model was established by intraplantar injection of CFA in C57BL/6J mice. After intrathecal injection of PF daily for 8 consecutive days, thermal and mechanical withdrawal thresholds, the levels of inflammatory factors TNF-α, IL-1β and IL-6, microglial activity, and the expression of Akt-NF-κB signaling pathway in the spinal cord tissue were detected by animal ethological test, cell culture, enzyme-linked immunosorbent assay, immunofluorescence histochemistry, and western blot. Results: PF inhibited the spinal microglial activation in the CFA-induced pain model. The production of proinflammatory cytokines was decreased in the central nervous system after PF treatment both in vivo and in vitro. PF further displayed a remarkable effect on inhibiting the activation of Akt-NF-κB signaling pathway in vivo and in vitro. Conclusion: These results suggest that PF is a potential therapeutic agent for inflammatory pain and merits further investigation.
“…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].…”
Background/Aims: Paeoniflorin (PF) is known to have anti-inflammatory and paregoric effects, but the mechanism underlying its analgesic effect remains unclear. The aim of this study was to clarify the effect of PF on Freund’s complete adjuvant (CFA)-induced inflammatory pain and explore the underlying molecular mechanism. Methods: An inflammatory pain model was established by intraplantar injection of CFA in C57BL/6J mice. After intrathecal injection of PF daily for 8 consecutive days, thermal and mechanical withdrawal thresholds, the levels of inflammatory factors TNF-α, IL-1β and IL-6, microglial activity, and the expression of Akt-NF-κB signaling pathway in the spinal cord tissue were detected by animal ethological test, cell culture, enzyme-linked immunosorbent assay, immunofluorescence histochemistry, and western blot. Results: PF inhibited the spinal microglial activation in the CFA-induced pain model. The production of proinflammatory cytokines was decreased in the central nervous system after PF treatment both in vivo and in vitro. PF further displayed a remarkable effect on inhibiting the activation of Akt-NF-κB signaling pathway in vivo and in vitro. Conclusion: These results suggest that PF is a potential therapeutic agent for inflammatory pain and merits further investigation.
“…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.…”
Background/Aims: Spinal dorsal horn (SDH) is one of the most important regions for analgesia produced by endomorphin-2 (EM2), which has a higher affinity and specificity for the µ-opioid receptor (MOR) than morphine. Many studies have focused on substantia gelatinosa (SG, lamina II) neurons to elucidate the cellular basis for its antinociceptive effects. However, the complicated types and local circuits of interneurons in the SG make it difficult to understand the real effects of EM2. Therefore, in the present study, we examined the effects of EM2 on projection neurons (PNs) in lamina I. Methods: Tracing, immunofluoresence, and immunoelectron methods were used to examine the morphological connections between EM2-immunoreactive (-ir) terminals and PNs. By using in vitro whole cell patch clamp recording technique, we investigated the functional effects of EM2 on PNs. Results: EM2-ir afferent terminals directly contacted PNs projecting to the parabrachial nucleus in lamina I. Their synaptic connections were further confirmed by immunoelectron microscopy, most of which were asymmetric synapses. It was found that EM2 had a strong inhibitory effect on the frequency, but not amplitude, of the spontaneous excitatory postsynaptic current (sEPSC) of the spinoparabrachial PNs in lamina I, which could be reversed by MOR antagonist CTOP. However, their spontaneous inhibitory postsynaptic current (sIPSC) and intrinsic properties were not changed after EM2 application. Conclusion: Applying EM2 to the SDH could produce analgesia through inhibiting the activities of the spinoparabrachial PNs in lamina I by reducing presynaptic neurotransmitters release from the primary afferent terminals.
“…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 ) .…”
Section: Fluorinated Amino Acids For Influencing the Stability Of mentioning
The decoration of organic compounds with fluorine substituents is a strategy well‐known to medicinal chemists. Around 25 % of drugs on the market contain at least one fluorine atom, as fluorine's unique properties very often produce effects that cannot be achieved by any other known functional group. The changes in molecular properties due to the incorporation of fluorine most relevant to medicinal chemistry are conformation, pKa values of neighboring functional groups, and interaction with proteins and membranes. The introduction of fluorine dramatically impacts these and in turn the pharmacokinetics and biological half‐lives of not only small molecules but peptides, which show high binding affinity and selectivity for their target and are, therefore, also desirable lead compounds in drug development. Unfortunately, several factors can limit the efficacy of peptides and biologicals including low bioavailability and protease digestion. Although the literature has numerous examples showing that fluorine can improve the latter aspect, there are also cases to the contrary. This review aims to provide an overview of the influence of fluorinated amino acids on the proteolytic stability of peptides.
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