The first structure-activity relationship study of oxytocin as a positive allosteric modulator for the µ opioid receptor.

Positive allosteric modulators (PAMs) of G protein-coupled receptors (GPCRs) have drawn attention as novel drug candidates. PAMs can enhance the activities of endogenous agonists which are not only secreted at appropriate times and in parts of the body, but also are immediately metabolized. Therefore, they are expected to show fewer side effects than exogeneous orthosteric ligands. Recently, we have reported that oxytocin (OT) functioned as a PAM of the µ opioid receptor (MOR) which was one of the most potent targets for analgesics. OT is thus thought to be a useful compound for the development of novel analgesics. In this study, several OT analogs were synthesized and evaluated with an intact cell-based assay to investigate the crucial structures of OT for exerting the PAM activity. The assay results indicated that the cyclic structure formed by an intramolecular disulfide bond and the three C-terminal residues containing a small Gly residue of OT were essential for their function as a MOR-PAM. Intriguingly, two analogs having an amide or an ethylene tether instead of the intramolecular disulfide bridge did not have any PAM effects. The results suggested that the disulfide linkage of OT would be a key structure for exerting the PAM activity at the MOR.

Oxytocin Is a Positive Allosteric Modulator of κ-Opioid Receptors but Not δ-Opioid Receptors in the G Protein Signaling Pathway.

Oxytocin (OT) influences various physiological functions such as uterine contractions, maternal/social behavior, and analgesia. Opioid signaling pathways are involved in one of the analgesic mechanisms of OT. We previously showed that OT acts as a positive allosteric modulator (PAM) and enhances µ-opioid receptor (MOR) activity. In this study, which focused on other opioid receptor (OR) subtypes, we investigated whether OT influences opioid signaling pathways as a PAM for δ-OR (DOR) or κ-OR (KOR) using human embryonic kidney-293 cells expressing human DOR or KOR, respectively. The CellKeyTM results showed that OT enhanced impedance induced by endogenous/exogenous KOR agonists on KOR-expressing cells. OT did not affect DOR activity induced by endogenous/exogenous DOR agonists. OT potentiated the KOR agonist-induced Gi/o protein-mediated decrease in intracellular cAMP, but did not affect the increase in KOR internalization caused by the KOR agonists dynorphin A and (-)-U-50488 hydrochloride (U50488). OT did not bind to KOR orthosteric binding sites and did not affect the binding affinities of dynorphin A and U50488 for KOR. These results suggest that OT is a PAM of KOR and MOR and enhances G protein signaling without affecting ß-arrestin signaling. Thus, OT has potential as a specific signaling-biased PAM of KOR.

The mediating effect of activity restriction on the relationship between perceived physical symptoms and depression in cancer survivors.

PURPOSE: Several studies have explored factors causing depression in cancer survivors, including perceived physical symptoms. Another critical factor in the depression symptomatology of cancer survivors is activity restriction (AR). We investigated how AR mediate the effects of perceived pain and fatigue on depression in cancer survivors. METHODS: Cancer survivors (n = 61; mean age 56.16 years) that were recruited through cancer support groups in Japan participated in this study. Participants completed a battery of questionnaires comprising demographic and clinical information, the Pain Catastrophizing Scale, the Cancer Fatigue Scale, the Activity Restriction Scale for Cancer Patients, and the Hospital Anxiety and Depression Scale. RESULTS: Mediation analysis indicated that AR partially mediates the effect of pain on depression. Direct paths from pain to AR, AR to depression, and pain to depression were significant (P < .005). Moreover, indirect paths from pain to AR, AR to depression, and pain to depression were also significant at the 95% level [0.04-0.13]. However, AR did not mediate the effect of fatigue on depression, and fatigue had a significant direct path to both AR and depression (P < .005). CONCLUSION: This study aimed to explore the mediating effect of AR in the relationships of perceived pain and fatigue and depression in cancer survivors. We found that AR mediates perceived pain to depression, however not for perceived fatigue. In addition, because AR was experienced in the face of any survivorship period, AR may need to be treated as a long-term effect of the cancer diagnosis.

Comparison between new-generation SiPM-based and conventional PMT-based TOF-PET/CT.

PURPOSE: This study aimed to determine whether the SiPM-PET/CT, Discovery MI (DMI) performs better than the PMT-PET/CT system, Discovery 710 (D710). METHODS: The physical performance of both systems was evaluated using NEMA NU 2 standards. Contrast (%), uniformity and image noise (%) are criteria proposed by the Japanese Society of Nuclear Medicine (JSNM) for phantom tests and were determined in images acquired from Hoffman and uniform phantoms using the DMI and D710. Brain and whole-body [18F]FDG images were also acquired from a healthy male using the DMI and D710. RESULTS: The spatial resolution at 1.0cm off-center in the DMI and D710 was 3.91 and 4.52mm, respectively. The sensitivity of the DMI and D710 was 12.62 and 7.50cps/kBq, respectively. The observed peak noise-equivalent count rates were 185.6kcps at 22.5kBq/mL and 137.0kcps at 29.0kBq/mL, and the scatter fractions were 42.1% and 37.9% in the DMI and D710, respectively. The D710 had better contrast recovery and lower background variability. Contrast, uniformity and image noise in the DMI were 61.0%, 0.0225, and 7.85%, respectively. These outcomes were better than those derived from the D710 and satisfied the JSNM criteria. Brain images acquired by the DMI had better grey-to-white matter contrast and lower image noise at the edge of axial field of view. CONCLUSIONS: The DMI offers better sensitivity, performance under conditions of high count rates and image quality than the conventional PMT-PET/CT system, D710.

The complete mitochondrial genome of Anisakis pegreffii Campana-Rouget & Biocca, 1955, (Nematoda, Chromadorea, Rhabditida, Anisakidae) - clarification of mitogenome sequences of the Anisakis simplex species complex.

The complete mitochondrial genome of Anisakis pegreffii (former A. simplex A) was determined using the Illumina HiSeq platform. The genome was 14,002 bp in length made up of 36 mitochondrial genes (12 CDSs, 22 tRNAs, and 2 rRNAs). Phylogenetic analysis clarified the mitogenome sequences of the three sibling species of the A. simplex species complex, A. pegreffii, A. simplex sensu stricto and A. berlandi (former A. simplex C).

Reinforcing and discriminative stimulus properties of music in goldfish.

This paper investigated whether music has reinforcing and discriminative stimulus properties in goldfish. Experiment 1 examined the discriminative stimulus properties of music. The subjects were successfully trained to discriminate between two pieces of music--Toccata and Fugue in D minor (BWV 565) by J. S. Bach and The Rite of Spring by I. Stravinsky. Experiment 2 examined the reinforcing properties of sounds, including BWV 565 and The Rite of Spring. We developed an apparatus for measuring spontaneous sound preference in goldfish. Music or noise stimuli were presented depending on the subject's position in the aquarium, and the time spent in each area was measured. The results indicated that the goldfish did not show consistent preferences for music, although they showed significant avoidance of noise stimuli. These results suggest that music has discriminative but not reinforcing stimulus properties in goldfish.