http://nova.newcastle.edu.au/vital/access/services/Feed ${session.getAttribute("locale")} 5 http://nova.newcastle.edu.au/vital/access/manager/Repository/uon:11118 Opioids have been discovered to have Toll-like receptor (TLR) activity, beyond actions at classical opioid receptors. This raises the question whether other pharmacotherapies for pain control may also possess TLR activity, contributing to or opposing their clinical effects. We document that tricyclics can alter TLR4 and TLR2 signaling. In silico simulations revealed that several tricyclics docked to the same binding pocket on the TLR accessory protein, myeloid differentiation protein 2 (MD-2), as do opioids. Eight tricyclics were tested for effects on TLR4 signaling in HEK293 cells over-expressing human TLR4. Six exhibited mild (desipramine), moderate (mianserin, cyclobenzaprine, imiprimine, ketotifen) or strong (amitriptyline) TLR4 inhibition, and no TLR4 activation. In contrast, carbamazepine and oxcarbazepine exhibited mild and strong TLR4 activation, respectively, and no TLR4 inhibition. Amitriptyline but not carbamazepine also significantly inhibited TLR2 signaling in a comparable cell line. Live imaging of TLR4 activation in RAW264.7 cells and TLR4-dependent interleukin-1 release from BV-2 microglia revealed that amitriptyline blocked TLR4 signaling. Lastly, tricyclics with no (carbamazepine), moderate (cyclobenzeprine), and strong (amitriptyline) TLR4 inhibition were tested intrathecally (rats) and amitriptyline tested systemically in wildtype and knockout mice (TLR4 or MyD88). While tricyclics had no effect on basal pain responsivity, they potentiated morphine analgesia in rank-order with their potency as TLR4 inhibitors. This occurred in a TLR4/MyD88-dependent manner as no potentiation of morphine analgesia by amitriptyline occurred in these knockout mice. This suggests that TLR2 and TLR4 inhibition, possibly by interactions with MD2, contributes to effects of tricyclics in vivo. These studies provide converging lines of evidence that several tricyclics or their active metabolites may exert their biological actions, in part, via modulation of TLR4 and TLR2 signaling and suggest that inhibition of TLR4 and TLR2 signaling may potentially contribute to the efficacy of tricyclics in treating chronic pain and enhancing the analgesic efficacy of opioids. 2012-07-24T03:36:48.607Z ]]> http://nova.newcastle.edu.au/vital/access/manager/Repository/uon:451 The aim of this study was to determine whether sensitization occurred to morphine withdrawal. Guinea-pigs were treated twice daily with increasing doses of morphine (10-100 mg/kg s.c.) for 3 days followed by injection of morphine 100 mg/kg on the fourth day. Sixty min after the last morphine injection, animals were withdrawn from morphine with naltrexone, 15 mg/kg s.c., and locomotor activity and all other behaviours scored over 90 min. Animals were then rested for 3 days. This procedure was repeated twice over the next 2 weeks. Control animals were treated with saline for the first two treatment cycles. Guinea-pigs subjected to three cycles of morphine withdrawal showed a significant increase in the total number of withdrawal behaviour counts over the 90-min observation period following the third cycle of withdrawal compared with the first and second withdrawal cycles. However, locomotor activity, a major sign of morphine withdrawal in guinea-pigs, was not significantly increased. Fos-LI was markedly increased in the repeatedly withdrawn animals in several brain regions, including amygdala, dorsal striatum, thalamus, ventral tegmental area, and ventrolateral periaqueductal gray area. It is concluded that sensitization to morphine withdrawal occurs in guinea-pigs. 2010-04-27T05:47:31.979Z ]]> http://nova.newcastle.edu.au/vital/access/manager/Repository/uon:4346 Background: Specific antidotes (eg, naloxone, flumazenil, cyproheptadine and benzodiazepines) are available for the management of certain recreational drug-induced toxicities. Some controversies surround the use of some of these antidotes, especially flumazenil in benzodiazepine toxicity. There are no previously published data on doctors' knowledge of the use of these specific antidotes. Methods: A questionnaire survey was designed to determine internal/emergency medicine doctors' knowledge of the appropriate use of antidotes in the management of clinical scenarios of acutely poisoned patients. For nine simulated clinical scenarios of acute toxicity from recreational drugs (benzodiazepines, cocaine, N-methyl-L-(3, 4-methylene-dioxyphenyl)-2-aminopropane (MDMA)-induced serotonin toxicity and opioids), they were asked to indicate whether the suggested antidote and route of administration were correct. Results: 42 physicians of all grades completed the questionnaire. The mean correct score was 5.4 (SD 1.1) (median 6, interquartile range 5-7). The percentages correct for the various clinical scenarios were 68.3% for opioid toxicity, 81% for benzodiazepine toxicity, 28.6% for MDMA-induced serotonin toxicity and 70.2% for cocaine toxicity. Doctors were more likely to record an answer of "unsure'' for the use of cyproheptadine in ST serotonin toxicity (28.6%) compared with the use of the other antidotes (1.4%; p < 0.001). Conclusion: Knowledge of the appropriate use of antidotes in recreational drug toxicity is not consistent, with poorer knowledge on the use of newer antidotes such as cyproheptadine in serotonin toxicity. Education is required both to increase overall knowledge on the use of specific antidotes in the management of recreational drug-induced toxicity, as well as focusing on newer antidotes such as cyproheptadine. 2010-04-27T05:04:43.751Z ]]>