Antidepressants Inhibit P2X4 Receptor Function: a Possible Involvement in Neuropathic Pain Relief

BACKGROUND: Neuropathic pain is characterized by pain hypersensitivity to innocuous stimuli (tactile allodynia) that is nearly always resistant to known treatments such as non-steroidal anti-inflammatory drugs or even opioids. It has been reported that some antidepressants are effective for treating neuropathic pain. However, the underlying molecular mechanisms are not well understood. We have recently demonstrated that blocking P2X(4 )receptors in the spinal cord reverses tactile allodynia after peripheral nerve injury in rats, implying that P2X(4 )receptors are a key molecule in neuropathic pain. We investigated a possible role of antidepressants as inhibitors of P2X(4 )receptors and analysed their analgesic mechanism using an animal model of neuropathic pain. RESULTS: Antidepressants strongly inhibited ATP-mediated Ca(2+ )responses in P2X(4 )receptor-expressing 1321N1 cells, which are known to have no endogenous ATP receptors. Paroxetine exhibited the most powerful inhibition of calcium influx via rat and human P2X(4 )receptors, with IC(50 )values of 2.45 μM and 1.87 μM, respectively. Intrathecal administration of paroxetine produced a striking antiallodynic effect in an animal model of neuropathic pain. Co-administration of WAY100635, ketanserin or ondansetron with paroxetine induced no significant change in the antiallodynic effect of paroxetine. Furthermore, the antiallodynic effect of paroxetine was observed even in rats that had received intrathecal pretreatment with 5,7-dihydroxytryptamine, which dramatically depletes spinal 5-hydroxytryptamine. CONCLUSION: These results suggest that paroxetine acts as a potent analgesic in the spinal cord via a mechanism independent of its inhibitory effect on serotonin transporters. Powerful inhibition on P2X(4 )receptors may underlie the analgesic effect of paroxetine, and it is possible that some antidepressants clinically used in patients with neuropathic pain show antiallodynic effects, at least in part via their inhibitory effects on P2X(4 )receptors

Robust circadian clocks from coupled protein modification and transcription-translation cycles

The cyanobacterium Synechococcus elongatus uses both a protein phosphorylation cycle and a transcription-translation cycle to generate circadian rhythms that are highly robust against biochemical noise. We use stochastic simulations to analyze how these cycles interact to generate stable rhythms in growing, dividing cells. We find that a protein phosphorylation cycle by itself is robust when protein turnover is low. For high decay or dilution rates (and co mpensating synthesis rate), however, the phosphorylation-based oscillator loses its integrity. Circadian rhythms thus cannot be generated with a phosphorylation cycle alone when the growth rate, and consequently the rate of protein dilution, is high enough; in practice, a purely post-translational clock ceases to function well when the cell doubling time drops below the 24 hour clock period. At higher growth rates, a transcription-translation cycle becomes essential for generating robust circadian rhythms. Interestingly, while a transcription-translation cycle is necessary to sustain a phosphorylation cycle at high growth rates, a phosphorylation cycle can dramatically enhance the robustness of a transcription-translation cycle at lower protein decay or dilution rates. Our analysis thus predicts that both cycles are required to generate robust circadian rhythms over the full range of growth conditions.Comment: main text: 7 pages including 5 figures, supplementary information: 13 pages including 9 figure

Current Status and Future Prospects of Proton MR Spectroscopy of the Breast with a 1.5T MR Unit

Proton MR spectroscopy of the mammary gland area is used to be considered in the realm of basic research, but as a result of the advances in MR techniques, it is now being performed in ordinary clinical practice. It is particularly noteworthy that useful clinical data are now being accumulated with 1.5T MR units, which are the standard units. We think that, at this point, it is very important to systematically review the techniques, clinical applications, and future prospects of proton MR spectroscopy. We have performed proton MR spectroscopy with a 1.5T MR unit in over 3000 cases at our hospital. In this paper, we will comment on the current status of proton MR spectroscopy of the breast, primarily in regard to differentiation between benign and malignant lesions and prediction of the efficacy of chemotherapy while describing the data obtained at our hospital