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.

Free radicals and oxidative stress play an important role in the pathogenesis of noiseinduced hearing loss (NIHL). Some ginseng monomers showed certain therapeutic effects in NIHL by scavenging free radicals. Therefore, we hypothesized that ginsenoside Rd (GSRd) may exert neuroprotective effects after noise-induced auditory system damage through a mechanism involving the SIRT1/PGC-1α signaling pathway. Fortyeight guinea pigs were randomly divided into four equal groups (normal control group, noise group, experimental group that received GSRd dissolved in glycerin through an intraperitoneal injection at a dose of 30 mg/kg body weight from 5 days before noise exposure until the end of the noise exposure period, and experimental control group). Hearing levels were examined by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE). Hematoxylin-eosin and Nissl staining were used to examine neuron morphology. RT-qPCR and western blotting analysis were used to examine SIRT1/PGC-1α signaling and apoptosis-related genes, including Bax and Bcl-2, in the auditory cortex. Bax and Bcl-2 expression was assessed via immunohistochemistry analysis. Superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) levels were determined using a commercial testing kit. Noise exposure was found to up-regulate ABR threshold and down-regulate DPOAE amplitudes, with prominent morphologic changes and apoptosis of the auditory cortex neurons (p < 0.01). GSRd treatment restored hearing loss and remarkably alleviated morphological changes or apoptosis (p < 0.01), concomitantly increasing Bcl-2 expression and decreasing Bax expression (p < 0.05). Moreover, GSRd increased SOD and GSH-Px levels and decreased MDA levels, which alleviated oxidative stress

Summary Noise‐induced structural and functional disorder of the liver has been realized, but the underlying mechanism remains to be characterized, which has limited the introduction of precautious measures. Over‐activation of acid sphingomyelinase (ASM)/ceramide (Cer) pathway takes centre stage in hepatocyte injury entailed by various stimulus. We aimed to investigate whether it mediated the noise elicited liver disorder on infrastructure, lipid metabolism, apoptosis, and oxidative stress. Mice were exposed to broad band noise (20–20k Hz, 90–110 dB) for 1, 3, 5 or 7 days by 3 hr/d. Doxepin hydrochloride (DOX), an ASM inhibitor was given by 5 mg/kg/d gavage. We showed that 5 or 7 days intense, broad band noise exposure caused significant infrastructure derangement and lipid droplets storage in hepatocytes. The content of cholesterol, free fatty acids or triglyceride was increased significantly in liver tissue upon noise stimulation. Moreover, the noise promoted apoptosis and superoxide generation in hepatocytes significantly, enhancing activity of aspartate aminotransferase (AST) or alanine amino transferase (ALT) in serum. Acid sphingomyelinase activity and Cer generation in liver tissue were elevated by noise exposure, which was normalized with DOX administrated. Accordingly, DOX alleviated steatosis, apoptosis, oxidative stress and enzymatic change in hepatocytes or serum of noise exposed mice substantially. In summary, our results suggest the ASM/Cer pathway contributes to the broad band noise elicited liver damage in mice.

Noise exposure relates to various pathological disorders including liver damage, preventive measures of which are being demanded. Hyperbaric oxygen treatment (HBOT), as a non‐invasive procedure, exerts convincing therapeutic potency on multiple liver diseases. The efficacy of HBOT in mitigating noise induced liver damage (NILD) and associated mechanisms would be elucidated here. Mice were subject to broad band noise (20–20k Hz, 90–110 dB) for 5 days by 3 hours/day. HBOT with 2.5 atmosphere absolute (ata) was employed before noise exposure. Morphology of liver tissue was examined by hematoxylin‐eosin (HE) staining. Oil Red O (ORO), transferase‐mediated dUTP nick end labelling (TUNEL) test and western blot were utilized to detect lipid accumulation, apoptotic cells and protein expression, respectively. Ceramide (Cer) level was assayed by immunohistochemistry (IHC) analysis. With noise exposure, conspicuous structural derangement and lipid deposition occurred in liver tissue of mice, which was alleviated significantly by the application of HBOT. Meanwhile, HBOT reduced the proportion of apoptotic hepatocytes, restraining the superoxide production in noise exposed mice. In view of underlying mechanisms, noise enhanced the acid sphingomyelinase (ASM) protein expression and the Cer generation in liver tissue of mice which was reversed substantially by HBOT. Altogether, HBOT ameliorates the structural and functional derangement of liver by neutralizing the ASM/Cer pathway in noise exposed mice.