AbstractThe primary cause of fatality in an opioid overdose is opioid induced respiratory depression. In addition to using opioids, polydrug use is common within the opioid using population, with ethanol being the most common additional drug of abuse, though another emerging class of co-abused drugs is the gabapentoids, including pregabalin. Ethanol has previously been shown to reverse morphine but not methadone induced tolerance to morphine respiratory depression, suggesting ethanol intrinsically interacts with maintained tolerance at the -opioid receptor. This thesis aimed to investigate the development of tolerance to abused opioids, the interaction of ethanol and pregabalin with opioid tolerance, and the potential molecular mechanisms required to maintain opioid tolerance.
Morphine, oxycodone, methadone and fentanyl all dose-dependently depressed respiration. Oxycodone did not display any contribution from - or -opioid receptors to its respiratory depressant effect. Fentanyl respiratory depression however, was significantly harder to antagonise than morphine respiratory depression, with a 10-fold greater dose of naloxone required, suggesting that the increase in fentanyl overdose deaths requires a re-assessment of first responder guidelines regarding naloxone administration to rescue respiration.
Prolonged treatment of mice with morphine, oxycodone and methadone were all able to induce tolerance to morphine respiratory depression. Morphine as the primary metabolite of heroin is likely to interact with both oxycodone and methadone induced tolerance suggesting cross-tolerance between abused opioids will offer some protection from overdose in humans.
Morphine and oxycodone tolerance were reversed by ethanol, pregabalin and PKC inhibition, suggesting commonality in the mechanisms by which these agonists induce tolerance. Methadone was contrarily not reversed by any of these treatments. Acute fentanyl tolerance was however reversed by GRK inhibition, indicating a potential delineation in mechanisms of tolerance dependent on agonist efficacy; with lower efficacy agonist predisposed toward G-protein dependent tolerance and higher efficacy agonist predisposed toward GRK dependent tolerance.
This thesis provides evidence for the continued necessity of understanding the drugs of concern in opioid polydrug abuse and assessing the reasons for enhanced comorbidity, beyond assuming summation of effect. Additionally, this thesis proposes PKC as the primary mediator of tolerance for both morphine and oxycodone tolerance to respiratory depression with fentanyl tolerance mediated by GRK. Further elucidation of polydrug abuse and mechanisms of tolerance will allow better care for opioid prescribed patients and opioid abusers, as well paving the way for the development of better opioid analgesics.
|Date of Award||23 Jan 2019|
|Supervisor||Eamonn P Kelly (Supervisor) & Graeme Henderson (Supervisor)|