Heteromers of μ-δ opioid receptors: new pharmacology and novel therapeutic possibilities

Several studies suggest that heteromerization between μ (MOP) and δ (DOP) opioid receptors modulates the signalling properties of the individual receptors. For example, whereas activation of MOP receptors by an agonist induces G protein-mediated signalling, the same agonist induces β-arrestin-mediated signalling in the context of the MOP-DOP receptor heteromer. Moreover, heteromer-mediated signalling is allosterically modulated by a combination of MOP and DOP receptor ligands. This has implications in analgesia given that morphine-induced antinociception can be potentiated by DOP receptor ligands. Recently reagents selectively targeting the MOP-DOP receptor heteromer such as bivalent ligands, antibodies or membrane permeable peptides have been generated; these reagents are enabling studies to elucidate the contribution of endogenously expressed heteromers to analgesia as well as to the development of side-effects associated with chronic opioid use. Recent advances in drug screening technology have led to the identification of a MOP-DOP receptor heteromer-biased agonist that activates both G protein-mediated and β-arrestin-mediated signalling. Moreover, this heteromer-biased agonist exhibits potent antinociceptive activity but with reduced side-effects, suggesting that ligands targeting the MOP-DOP receptor heteromer form a basis for the development of novel therapeutics for the treatment of pain. In this review, we summarize findings regarding the biological and functional characteristics of the MOP-DOP receptor heteromer and the in vitro and in vivo properties of heteromer-selective ligands.

LINKED ARTICLES

This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2     

Evaluation of the effect of miltefosine on Trichomonas vaginalis

Trichomonas vaginalis causes trichomoniasis in humans, a sexually transmitted disease commonly treated with metronidazole (MTZ). MTZ is known to cause undesirable side effects, and MTZ-resistant parasites have been reported. Thus, the development of an alternative treatment is desirable. Miltefosine (MLT) is an alkylphosphocholine synthetic lipid analogue that displays antiparasitic activity against Leishmania, Trypanosoma cruzi, Entamoeba histolytica, Acanthamoeba spp., Giardia lamblia, T. vaginalis and some fungi. Moreover, it has been used for oral treatment of visceral leishmaniosis in several countries. Here, we analysed the MLT-induced antiproliferative effect on T. vaginalis as well its effect on the fine structure and viability of the parasite. We observed a dose-dependent effect with an IC₅₀ of 14.5 and 20 μM after 24 and 48 h, respectively. Furthermore, reversibility assays demonstrated that new incubations were necessary in order to maintain the antiproliferative effect. Ultrastructural analyses demonstrated that MLT induced several alterations, including the appearance of wrinkled and rounded cells, membrane blebbing, intense vacuolization and nuclear condensation, all indicative of cell death by apoptosis. In addition, the quantitative analyses of the viability assays using combined markers of live and dead cells demonstrated that treatment with the IC₅₀ concentration of MLT significantly reduced the number of viable parasites compared with untreated cells. Taken together, these observations suggest that MLT is a promising compound for the treatment of trichomoniasis.     

Maximal heart rate assessment in recreational football players: A study involving a multiple testing approach

This study aimed at examining the suitability of a standard treadmill test (TT), popular intermittent field tests, and small‐sided football matches to induce maximal heart rate (HR_max) in recreational football players. Sixty‐six inactive untrained male subjects (age: 39.3 ± 5.8 years, VO_2max: 41.2 ± 6.2 mL kg^?1 min^?1, body mass: 81.9 ± 10.8 kg, height: 173.2 ± 6.4 cm) were evaluated. On separate occasions, the players were randomly submitted to a progressive VO_2max TT, to the Yo‐Yo intermittent endurance level 1 (YYIE1) and level 2 (YYIE2) tests, to the Yo‐Yo intermittent recovery level 1 (YYIR1) test, and to 7v7 (43 × 27 m pitch, 83 m²/player) football matches (45 minutes; 2‐4 matches/player). To ensure data consistency, exercise HR was recorded using the same HR monitors in all the experimental conditions. A total of 73%, 24%, 18%, 17%, and 30% of the players achieved their HR_max during the YYIE1, YYIE2, YYIR1, TT, and the small‐sided football matches, respectively. The probability of achieving HR_max increased proportionally to test duration, with 7.8 minutes as the cutoff time. Variations in HR_peak of ±2 b min^?1 should be regarded as of practical relevance. YYIE1 HR_peak provided the most accurate estimation of a subject's individual HR_max and much higher probability of reaching HR_max. Nevertheless, the results of this study suggest caution in considering a reference test for HR_max assessment in this population. The use of confirmation tests is still highly advisable when the test duration is shorter than 7.8 minutes. In this regard, field tests seem to be suitable and accurate for individual HR_max assessment in recreational football players.     

Advocacy care on HIV disclosure to children

Children with HIV are dependent on taking continuous medication and care, and family preparation is required when disclosing HIV. This study aimed to unveil families’ experiences with HIV disclosure to children under 13 years old. Eight family members who have disclosed HIV to seropositive children were interviewed in‐depth and individually. The fieldwork took place at a public paediatric outpatient hospital in Rio de Janeiro. The results showed that the family members’ discourse highlighted two ways of knowing their own condition and disclosing the condition of the children with HIV. First, they needed to address the communication of bad news and discover their own HIV status through their children's disease. Second, the disclosure was a process constituted by four stages: preparing for disclosure, identifying the time, deciding how and where to tell, and instilling silence after disclosure. They also recognized that nurses had a role in the process as part of an interprofessional team. Nurses can develop advocacy care and empower family members in the preparation of safe HIV disclosure. By systematizing and institutionalizing the care advocacy process, nurses may enable caretakers and children to participate in their therapeutic management, improving adherence to the treatment and self‐care with autonomy.     

Early and late effects of X-irradiation on submandibular gland: a morphological study in mice

BACKGROUND: Radiotherapy for head and neck cancers causes permanent salivary gland dysfunction and xerostomia. The aim of this study was to determine changes in mice submandibular glands after X-irradiation. METHODS: The submandibular glands of male C57BL/6 mice were locally X-irradiated in the head and neck region with a single dose of 7.5 or 15 Gy and analyzed morphologically and morphometrically at 1, 3, 6, 10, 40, and 90 days after irradiation. RESULTS: Two phases of gland reaction to irradiation have been noted. The first, early phase is observed up to 10 days after irradiation. The second, late phase was observed 90 days after irradiation. Also, a dose-related effect was noticed. The most prominent morphological changes were pyknotic nuclei, vacuolization of acinar cells and lysis of acini and granular convoluted tubules. Changes were detected at 3 and 6 days after irradiation followed by tissue regeneration. Ninety days after irradiation, prominent pathological changes (vacuolization and pyknotic nuclei of acinar cells, lysis of acini and granular convoluted tubules and edema) were detected, but the most remarkable change was disseminated mononuclear infiltration. Also, a statistically significant reduction in number of acinar cells was detected in both irradiated glands. CONCLUSIONS: Occurrence of disseminated mononuclear infiltration in gland during late post-irradiation phase makes the mouse model potentially better than the rat model for investigation of irradiation-induced salivary gland damage.     

Dimethyl sulfoxide and oxidative stress on cultures of human keratinocytes

OBJECTIVES:

The aim of the present study was to examine the protective action of the antioxidant dimethyl sulfoxide (DMSO) against the oxidative stress on keratinocyte cultures caused by glucose deprivation and hypoxia, using the concentration of malonyl dialdehyde existing in the cell culture as an indicator of the oxidative stress level.

METHODS:

Eighty flasks with cultured human keratinocytes in a confluent layer were divided into eight groups, including the following: culture medium with and without glucose, culture medium with and without the addition of DMSO, culture medium subjected and not subjected to hypoxia, and culture medium with a combination of these factors.

RESULTS AND CONCLUSIONS:

The statistical analysis of the results showed that DMSO proved to be an effective agent against the oxidative stress on cultures of keratinocytes under the experimental conditions studied.     

Nursing and costs management

This work intend to broach structural elements that motivate institutions and health professionals to know and develop studies about hospital costs, emphasize the subject importance for the nursing professional.