ity from increased systemic exposure, especially in patients with organ impairment.Opioids are potent analgesics, but their pain-relieving effects diminish with repeated use. The reduction in analgesic potency is a hallmark of opioid analgesic tolerance, which hampers opioid pain therapy. In the central nervous system, opioid analgesia is critically modulated by adenosine, a purine nucleoside implicated in the beneficial and detrimental actions of opioid medications. Here, we focus on the A3 adenosine receptor (A3 AR) in opioid analgesic tolerance. Intrathecal administration of the A3 AR agonist MRS5698 with daily systemic morphine in male rats attenuated the reduction in morphine antinociception over 7 days. In rats with established morphine tolerance, intrathecal MRS5698 partially restored the antinociceptive effects of morphine. However, when MRS5698 was discontinued, these animals displayed a reduced antinociceptive response to morphine. Our results suggest that MRS5698 acutely and transiently potentiates morphine antinociception in tolerant rats. By contrast, in morphine-naïve rats MRS5698 treatment did not impact thermal nociceptive threshold or affect antinociceptive response to a single injection of morphine. Furthermore, we found that morphine-induced adenosine release in cerebrospinal fluid was blunted in tolerant animals, but total spinal A3 AR expression was not affected. Collectively, our findings indicate that spinal A3 AR activation acutely potentiates morphine antinociception in the opioid tolerant state. Given the increasing emergence of drug resistance in Plasmodium, new antimalarials are urgently required. P218 is an aminopyridine that inhibits dihydrofolate reductase being developed as a malaria chemoprotective drug. Assessing the effect of new compounds on cardiac intervals is key during early drug development to determine their cardiac safety. This double-blind, randomized, placebo-controlled, parallel group study evaluated the effect of P218 on electrocardiographic parameters following oral administration of seven single-ascending doses up to 1000 mg in 56 healthy volunteers. Participants were randomized to treatment or placebo at a 31 ratio. P218 was administered in the fasted state with standardized lunch served 4 hours after dosing. 12-lead ECGs were recorded in triplicate at regular intervals on the test day, and at 48, 72, 120, 168, 192 and 240 hours thereafter. Blood samples for pharmacokinetic evaluations were collected at similar time points. Concentration-effect modelling was used to assess the effect of P218 and its metabolites on cardiac intervals. Concentration-effect analysis showed that P218 does not prolong the QTcF, J-Tpeak or TpTe interval at all doses tested. No significant changes in QRS or PR intervals were observed. Two-sided 90% confidence intervals of subinterval effects of P218 and its metabolites were consistently below the regulatory concern threshold for all doses. Study sensitivity was confirmed by significant shortening of QTcF after a meal. Oral administration of P218 up to 1000 mg does not prolong QTcF and does not significantly change QRS or PR intervals, suggesting low risk for drug-induced proarrhythmia.Oral administration of P218 up to 1000 mg does not prolong QTcF and does not significantly change QRS or PR intervals, suggesting low risk for drug-induced proarrhythmia. Oro-facial pain is more prevalent in women than in men, and oestrogen may underlie this sex difference. Genistein reversed the potentiation of 17β-estradiol (E2) on glutamate-induced acute masseter nociceptive behaviour, but its role in dental experimental occlusal interference (EOI)-induced chronic masseter hyperalgesia remains unclear. This study aimed to investigate sex differences, and to explore the role and underlying mechanisms of genistein in E2-potentiated EOI-induced chronic masseter hyperalgesia in rats. Female and male rats were prepared to compare the sex differences of masseter hyperalgesia induced by EOI using a 0.4-mm-thick metal crown. Female rats were ovariectomised (OVX) and treated with E2 and genistein, followed by EOI. The head withdrawal threshold (HWT) was examined to assess masseter sensitivity. The protein expression of transient receptor potential vanilloid-1 (TRPV1) in the trigeminal ganglion (TG) was detected using western blotting. Immunofluorescence staining was used to reveal the colocalisation of oestrogen receptors (ERs) with TRPV1 and the percentage of TRPV1-positive neurons in the TG. To some extent, female rats displayed enhanced sensitivity to EOI-induced chronic masseter hyperalgesia compared with males. Female rats showed the lowest HWT in the pro-oestrus phase. Pre-treatment with genistein antagonised E2 potentiation in EOI-induced masseter hyperalgesia and blocked the effect of E2 by downregulating TRPV1 protein expression and the percentage of TRPV1-positive neurons in the TG. Female rats showed greater masseter hyperalgesia than males under EOI. Genistein antagonised the facilitation of EOI-induced chronic masseter hyperalgesia by E2 probably through inhibiting TRPV1 in the TG.Female rats showed greater masseter hyperalgesia than males under EOI. Genistein antagonised the facilitation of EOI-induced chronic masseter hyperalgesia by E2 probably through inhibiting TRPV1 in the TG.Inhibitors of bromodomain and extra-terminal motif (BET) proteins are emerging epigenetic therapeutics that suppress gene expressions that drive cancer and inflammation. The present study examined anti-inflammatory effects of a quinazoline-based BET inhibitor, CN210, in a murine ileitis model. CN210 was given orally 30 min before and 24 h after a subcutaneous administration of indomethacin. Macroscopic and histological evidences of ileitis, mucosal myeloperoxidase (MPO) activity and cytokine expressions were evaluated 48 h after the indomethacin administration. To further characterize the anti-inflammatory pathways modulated by CN210, its effects on RAW264 cells treated with lipopolysaccharide (LPS) were investigated. click here Competitive ligand binding and docking studies of CN210 to CREB-binding protein (CBP) and p300 were also performed. Oral administration of CN210 significantly reduced the severity of ileitis, normalized both proinflammatory MPO activity and concomitant cytokine expressions induced by indomethacin administration.