A major unresolved issue in treating pain is the paradoxical hyperalgesia produced by the gold-standard analgesic morphine and other opiates. We show here that hyperalgesia-inducing treatment with morphine causes downregulation of the K+-Cl− cotransporter KCC2, impairing Cl− homeostasis in spinal lamina l neurons. Restoring Eanion reversed the morphine-induced hyperalgesia without affecting tolerance. The hyperalgesia was also reversed by ablating spinal microglia. Morphine hyperalgesia, but not tolerance, required μ opioid receptor-dependent expression of P2X4 receptors (P2X4Rs) in microglia and μ-independent gating of the release of brain-derived neurotrophic factor (BDNF) by P2X4Rs. Blocking BDNF-TrkB signalling preserved Cl− homeostasis and reversed the hyperalgesia. Gene-targeted mice in which BDNF was deleted from microglia did not develop hyperalgesia to morphine. Yet, neither morphine antinociception nor tolerance was affected in these animals. Our findings dissociate morphine-induced hyperalgesia from tolerance and unveil the microglia-to-neuron P2X4-BDNF-KCC2 pathway as a therapeutic target to prevent hyperalgesia without affecting morphine analgesia.

Background: As good communication skills are crucial for doctor-patient interactions, it is recommended to incorporate them in medical school programs from the very beginning. On this basis medical schools in Germany introduced the OSCE (objective structured clinical examination) to examine and by this foster learning of communication skills as assessment drives learning. The aim of the study was to examine the development of the communication skills of medical students during an OSCE to investigate how communication competence has developed between different student cohorts. Methods: This study is a longitudinal trend study based on seven semester-cohorts, examining the communication skills of medical students in the OSCE both from the perspective of students and from the viewpoint of standardized patients (SP). Altogether, 1027 students from seven semester cohorts were asked to rate their own communication skills (self-perception) before the OSCE exam started. Here, sub-analyses were performed to outline a potential influence of previous history-taking group participation. The SP evaluated the students' communication skills in external perception during the OSCE exam at each station with history-taking or physical examinations. The communication skills in both groups were ascertained in the dimensions of empathy, content structure, verbal expression, and non-verbal expression. Results: Only in the dimension of non-verbal expression could a statistically significant change be found in students' self-perception over the years. Notably, the rating of communication skills as self-rated by the students has risen constantly, whereas they deteriorated from the perspective of standardized patients (SP). It has also been found that previous history-taking courses have a positive influence on the structural dimension of communication skills in particular. Conclusions: The results of this study support conclusions of other studies which also suggest differences between self-and external perception of medical students' communication skills. Nevertheless, students showed good overall communication skills in the four dimensions of empathy, content structure, verbal expression, and non-verbal expression, as demonstrated in a longitudinal trend study over seven semesters. However, we noted that externally rated empathy levels declined over the semester cohorts, suggesting the need for new priorities to be set in student teaching.

One operational measure of sensorimotor gating that is deficient in many psychiatric disorders is prepulse inhibition (PPI) of the startle response. To investigate the role of dopamine D1 and D2 receptors within the nucleus accumbens (NAC) in sensorimotor gating in mice, we infused dopamine D1 and D2 receptor agonists (dihydrexidine and quinpirole respectively) directly into the NAC and measured the effects on PPI and on prepulse facilitation. Quinpirole infusions increased PPI and attenuated prepulse facilitation, whereas dihydrexidine had no effects. These results stand in contrast to data after systemic injections in mice and rats and intra-accumbal infusions in rats, suggesting that the role of dopamine D2 receptors within the NAC in mice differs from their role in rats.

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