Opioid receptor modulation of pro-inflammatory cytokine production is vital for host defense and the inflammatory response. Previous results have shown the mu-opioid receptor (MOR) selective agonist, DAMGO, has the capacity to increase the expression of the pro-inflammatory chemokines, CCL2/MCP-1, CCL5/RANTES and CXCL10/IP-10 in peripheral blood mononuclear cells (PBMCs). We have shown that MOR activation is able to induce the expression of TGF-β, and TGF-β appears to be required for induction of CCL5 following MOR activation. This work suggests a novel role for TGF-β in the inflammatory response. NF-κB is a transcription factor that plays a pivotal role in inflammation and the immune response. We have found that NF-kB inhibitors can prevent the MOR-induced activation of CCL2 and CCL5, and that the NF-kB subunit, p65, is phosphorylated at serine residues 311 and 536 in response to μ-opioid receptor activation. In vivo, DAMGO administration can induce binding of p. 65 to the enhancer region of the CCL2 promoter. Furthermore, we demonstrate that PKCζ is phosphorylated following DAMGO-induced MOR activation and, is essential for NF-kB activity as well as CCL2 expression and transcriptional activity. In conclusion, these data suggest a pro-inflammatory role for MOR which involves NF-κB activation and PKCζ as well as a novel role for TGF-β as a regulator of pro-inflammatory chemokines. / Molecular Biology and Genetics

The original publication is available at http://www.samj.org.za / Medical practitioners in South Africa are increasingly confronted with requests to treat patients with opioid use disorders. Many do not possess the required knowledge and skills to deal with these patients effectively. This overview of the medical treatment of opioid dependence was compiled by an elected working group of doctors working in the field of substance dependence. Recommendations are based on current best practice derived from scientific evidence and consensus of the working group, but should never replace individual clinical judgement. / Publishers' version

BACKGROUND:Opioids are the cornerstone of treatment for moderate to severe pain, but chronic use leads to maladaptations that include: tolerance, dependence and opioid-induced hyperalgesia (OIH). These responses limit the utility of opioids, as well as our ability to control chronic pain. Despite decades of research, we have no therapies or proven strategies to overcome this problem. However, murine haplotype based computational genetic mapping and a SNP data base generated from analysis of whole-genome sequence data (whole-genome HBCGM), provides a hypothesis-free method for discovering novel genes affecting opioid maladaptive responses.RESULTS:Whole genome-HBCGM was used to analyze phenotypic data on morphine-induced tolerance, dependence and hyperalgesia obtained from 23 inbred strains. The robustness of the genetic mapping results was analyzed using strain subsets. In addition, the results of analyzing all of the opioid-related traits together were examined. To characterize the functional role of the leading candidate gene, we analyzed transgenic animals, mRNA and protein expression in behaviorally divergent mouse strains, and immunohistochemistry in spinal cord tissue. Our mapping procedure identified the allelic pattern within the netrin-1 receptor gene (Dcc) as most robustly associated with OIH, and it was also strongly associated with the combination of the other maladaptive opioid traits analyzed. Adult mice heterozygous for the Dcc gene had significantly less tendency to develop OIH, become tolerant or show evidence of dependence after chronic exposure to morphine. The difference in opiate responses was shown not to be due to basal or morphine-stimulated differences in the level of Dcc expression in spinal cord tissue, and was not associated with nociceptive neurochemical or anatomical alterations in the spinal cord or dorsal root ganglia in adult animals.CONCLUSIONS:Whole-genome HBCGM is a powerful tool for identifying genes affecting biomedical traits such as opioid maladaptations. We demonstrate that Dcc affects tolerance, dependence and OIH after chronic opioid exposure, though not through simple differences in expression in the adult spinal cord.

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There has been much evidence in recent years to suggest that the kappa opioid receptor plays a significant role in mediating a number of behavioural disorders including drug abuse and depression. Previous in vitro evaluation within the group of secondary and tertiary amines derived from 2-amino-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-7-ol has suggested that all behave as pure opioid antagonists. These findings prompted further synthetic and pharmacological investigations of this scaffold, with the eventual aim of developing a short-acting selective kappa opioid antagonist to further probe the receptor.

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Methadone is the foremost, long-standing pharmacological treatment for opioid addiction. It has been shown to have considerable cost benefit to the community and to decrease mortality. Despite methadone's decades-long use, much is still unknown regarding its clinical pharmacology, particularly during the induction phase of Methadone Maintenance Treatment (MMT). Contrary to previous reports, I found systemic methadone clearance does not increase significantly between induction and steady state phases of MMT, and did not approach the previously reported 3-fold increase. Clinical dose prescription based on the premise of metabolism auto-induction could increase risk of respiratory depression. Significant differences between R- and S-methadone pharmacokinetics showed the importance of stereoselective measurement in a clinical situation and significant plasma concentration-effect relationships demonstrated their potential influence on induction pharmacodynamics. Small increases in CYP3A4 activity as measured by the Erythromycin Breath Test from Day 1 to Day 40 of MMT were not correlated with changes in methadone clearance. CYP3A4 activities were informative but would be insufficient for use as a sole predictor of methadone clearance during MMT. Clinically significant respiratory depression occurred in 20% of subjects, at times of peak plasma R-methadone concentrations, after reports of withdrawal symptoms at pre-dose sampling times, and irrespective of illicit opioid use. Utilisation of both respiratory rate and blood oxygen saturation measurements provided a good indication of respiratory risk for individuals. Although prior opioid use was a strong predictor of continued use during MMT, adoption of a new equation ("abc") and comprehensive documentation of each individual's MMT may increase prediction of MMT success. Even in light of recent advances in opioid substitution therapies, MMT's advantages ensure it is still at the forefront of addiction treatment. Careful choice of methodology enabled narrowing of this investigation to those factors most relevant in methadone pharmacology and most responsible for MMT success or failure, and therefore extending previous knowledge of this area. Such data might be utilised to develop a clinically applicable model for MMT, and help provide clients with a safe and uncomplicated transition from heroin use to methadone induction in the future. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1269301 / Thesis (Ph.D.) -- School of Medical Sciences, 2007

It was hypothesized that a metabolite of morphine, morphine-3-glucuronide (M3G), contributes to the expression of symptoms seen during withdrawal from morphine. To test this hypothesis, the behaviors observed during precipitated withdrawal from morphine and sufentanil were compared. Sufentanil was chosen because, like morphine, it acts primarily at the mu opioid receptor, but has different metabolites. Differences in the abstinence syndromes produced by the two drugs may therefore be attributable to the actions of metabolites, rather than the primary opioid actions of morphine and sufentanil. Although there were some differences in the occurrence of symptoms, morphine and sufentanil withdrawal were very similar. Therefore, the evidence was inconclusive as to the contribution of metabolites during withdrawal. / Systemic administration of M3G alone and in combination with morphine produced no withdrawal-like behaviors. However, when these drugs were given centrally, withdrawal-like behaviors were observed in conjunction with seizures. The seizures were not attenuated by naloxone (but were alleviated by an anti-convulsant), indicating that they were not mediated by opioid receptors. The behaviors resembled those seen by previous investigators following high doses of morphine. The results suggest that M3G may play a role in the toxic effects of high doses of morphine.

Background: One population prone to aspiration pneumonia and impaired cough is the postoperative patient. Postoperative pneumonia is the third most common complication among surgical patients after urinary tract and wound infections (Wren, Martin, Yoon, & Bech, 2010). A patient who has their surgical course complicated by aspiration pneumonia has increased morbidity, increased length of hospital stay and places greater demands on the health system. Mortality rates are cited as high as 70% (Wren, et al., 2010). Despite the prevalence of postoperative pneumonia and the high morbidity and mortality rates, little is known about the effect of anaesthesia on swallowing and airway protection. This study investigated the effect of clinical doses of fentanyl on suppressed cough reflex in healthy participants. Materials and Methods: After receiving ethical approval, 14 young, healthy participants gave informed written consent and completed the study protocol. Each participant received a total of 2 mcg/kg of fentanyl in four doses administered at five-minute intervals. Fentanyl effect site concentrations (ESC) were estimated using a standard pharmacokinetic model. During the administration period, suppressed cough response testing (SCR) with nebulised citric acid was performed after each fentanyl dose. Citric acid was presented in increments of 0.2M from each participant’s baseline cough response until a present-strong response was achieved. During the post-administration period, SCR was compared with reducing effect site concentrations to determine the time course for resolution of cough suppression. Results: Suppressed cough threshold increased and decreased in parallel with modeled fentanyl effect site concentrations. Mean citric acid concentration increased from 0.5M at baseline to 0.6M after 0.5 mcg/kg of fentanyl, 0.7 M after 1 mcg/kg of fentanyl, 0.9M after 1.5 mcg/kg of fentanyl and 1.2M after 2 mcg/kg of fentanyl. Predicted effect site concentrations after final doses of fentanyl (2 mcg/kg) were 1.89 ng/mL (1.81-1.96), well within the range seen clinically in the postoperative period. After the final dose of fentanyl, participants had on average 3.4 increments of change in their cough response (at increments of 0.2M). Conclusion: SCR testing with citric acid is sensitive enough to mirror changes in fentanyl ESC in healthy, young participants. The degree of reflex suppression seen has been associated with an 8-fold increase in aspiration risk in the general medical patient with dysphagia (Miles, Moore, McFarlane, Lee, Allen, Huckabee, 2013). Further research into the application of SCR in the postoperative period may help clinical decisions regarding safety to commence oral intake.