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The ability of oxytocin (OT) to interact with the dopaminergic system through facilitatory D2-OT receptor (OTR) receptor-receptor interaction in the limbic system is increasingly considered to play roles in social or emotional behavior, and suggested to serve as a potential therapeutic target. Although roles of astrocytes in the modulatory effects of OT and dopamine in the central nervous system are well recognized, the possibility of D2-OTR receptor-receptor interaction in astrocytes has been neglected. In purified astrocyte processes from adult rat striatum, we assessed OTR and dopamine D2 receptor expression by confocal analysis. The effects of activation of these receptors were evaluated in the processes through a neurochemical study of glutamate release evoked by 4-aminopyridine; D2-OTR heteromerization was assessed by co-immunoprecipitation and proximity ligation assay (PLA). The structure of the possible D2-OTR heterodimer was estimated by a bioinformatic approach. We found that both D2 and OTR were expressed on the same astrocyte processes and controlled the release of glutamate, showing a facilitatory receptor-receptor interaction in the D2-OTR heteromers. Biochemical and biophysical evidence confirmed D2-OTR heterodimers on striatal astrocytes. The residues in the transmembrane domains four and five of both receptors are predicted to be mainly involved in the heteromerization. In conclusion, roles for astrocytic D2-OTR in the control of glutamatergic synapse functioning through modulation of astrocytic glutamate release should be taken into consideration when considering interactions between oxytocinergic and dopaminergic systems in striatum.

Background: Roles of astrocytes in the modulatory effects of oxytocin (OT) in central nervous system are increasingly considered. Nevertheless, OT effects on gliotransmitter release have been neglected. Methods: In purified astrocyte processes from adult rat striatum, we assessed OT receptor (OTR) and adenosine A2A receptor expression by confocal analysis. The effects of receptors activation on glutamate release from the processes were evaluated; A2A-OTR heteromerization was assessed by co-immunoprecipitation and PLA. Structure of the possible heterodimer of A2A and OT receptors was estimated by a bioinformatic approach. Results: Both A2A and OT receptors were expressed on the same astrocyte processes. Evidence for A2A-OTR receptor-receptor interaction was obtained by measuring the release of glutamate: OT inhibited the evoked glutamate release, while activation of A2A receptors, per se ineffective, abolished the OT effect. Biochemical and biophysical evidence for A2A-OTR heterodimers on striatal astrocytes was also obtained. The residues in the transmembrane domains 4 and 5 of both receptors are predicted to be mainly involved in the heteromerization. Conclusions: When considering effects of OT in striatum, modulation of glutamate release from the astrocyte processes and of glutamatergic synapse functioning, and the interaction with A2A receptors on the astrocyte processes should be taken into consideration.

The aim of this study was the identification of specific proteomic profiles, related to a restored cystic fibrosis transmembrane conductance regulator (CFTR) activity in cystic fibrosis (CF) leukocytes before and after ex vivo treatment with the potentiator VX770. We used leukocytes, isolated from CF patients carrying residual function mutations and eligible for Ivacaftor therapy, and performed CFTR activity together with proteomic analyses through micro-LC–MS. Bioinformatic analyses of the results obtained revealed the downregulation of proteins belonging to the leukocyte transendothelial migration and regulation of actin cytoskeleton pathways when CFTR activity was rescued by VX770 treatment. In particular, we focused our attention on matrix metalloproteinase 9 (MMP9), because the high expression of this protease potentially contributes to parenchyma lung destruction and dysfunction in CF. Thus, the downregulation of MMP9 could represent one of the possible positive effects of VX770 in decreasing the disease progression, and a potential biomarker for the prediction of the efficacy of therapies targeting the defect of Cl− transport in CF.

Objective. Opioid therapy in patients with chronic noncancer pain must be preceded by evaluation of the risk of opioid misuse. The aim of this study was to evaluate the predictive validity of the Italian translation of the Pain Medication Questionnaire (PMQ) and of the Diagnosis Intractability Risk and Efficacy Score (DIRE) in chronic pain patients. Design. 75 chronic noncancer pain patients treated with opioids were enrolled and followed longitudinally. Risk of opioid misuse was evaluated through PMQ, DIRE, and the physician’s clinical evaluation. Pain experience and psychological characteristics were assessed through specific self-report instruments. At follow-ups, pain intensity, aberrant drug behaviors, and presence of the prescribed opioid and of illegal substances in urine were also checked. Results. PMQ demonstrated good internal consistency (Cronbach’s α=0.77) and test-retest reliability (r=0.86). Significant correlations were found between higher PMQ scores and the number of aberrant drug behaviors detected at 2-, 4-, and 6-month follow-ups (P<0.01). Also the DIRE demonstrated good predictive validity. Conclusions. The results obtained with specific tools are more reliable than the clinician’s evaluation alone in predicting the risk of opioid misuse; regular monitoring and psychological intervention will contribute to improving compliance and outcome of long-term opioid use.

When pain becomes chronic it assumes an almost absolute central role in the disease experience: it characterises and qualifies it, and constantly interferes with the daily life of the patient (Bonica, 1992). It could be said that chronic pain becomes a disease in itself in the patient’s perception; daily activities, interpersonal relationships, feelings, are profoundly disturbed by living with pain (Loeser, 2000). While modern medicine has made notable progress in understanding, diagnosing and treating chronic pain, it continues to be a very widespread problem that significantly compromises the professional, social and family life of the patient, and is often not adequately managed (Manchikanti et al., 2010). The problem of inadequately managed pain is still a considerable one (Breivik et al., 2006), although the World Health Organization [WHO] (1990) has stated that to be pain free should be considered a right of every patient. The consequences of inadequately treated pain not only have an impact in terms of the physical and psychological suffering of the patient and his family, they also have an enormous economic impact on society as a whole (Brennan et al., 2007; van Leeuwen et al., 2006). Options for the treatment of chronic pain include both pharmacological treatments (e.g. non steroidal anti-inflammatory drugs, opioids) and non-pharmacological treatments (e.g. physical therapies, acupuncture, cognitive-behavioural therapy, surgical procedures). Choice of treatment should be guided by a complex initial assessment of the patient, which includes the collection of historical information (e.g. pain history and treatments tried, surgical procedures, psychosocial and family history), a physical examination and appropriate diagnostic tests (Passik, 2009). Opioids are considered one of the most efficacious groups of drugs in treating mediumsevere pain (Portenoy, 2000), and their use can result in a significant improvement in the patient’s quality of life (Dillie et al., 2008); while there is unanimous agreement on their use in acute and cancer pain, their long-term use for non-cancer chronic pain remains controversial (Dews & Mekhail, 2004; Manchikanti et al., 2010; Rosenblum et al., 2008). The discovery of the properties of these substances, and their use as analgesics, is lost in the mists of time: the Sumerians were starting to cultivate poppies as early as 3400 B.C. (Booth, 1986, as cited in Dews & Mekhail, 2004). In 1803, Friedrich Serturner, a German pharmacist