How does ethanol alter opioid tolerance?

Ethanol, consumed in alcoholic beverages, is frequently found to be present along with heroin or methadone in opioid overdose fatalities. It is therefore extremely important to determine exactly how ethanol may be interacting with opioid drugs to enhance the dangers of their illicit use.

There is evidence from our own work to suggest that acute exposure to low doses of ethanol can reduce tolerance to the respiratory depressant and analgesic actions of morphine whereas chronic ethanol consumption appears to reduce the analgesic effectiveness of opioid drugs. This suggests that there may be differences in the way ethanol affects the actions of opioids depending upon the nature of ethanol consumption (intermittent v chronic intake). The aim of the research described in this proposal is therefore to determine at the molecular, cellular and behavioural levels how acute and chronic ethanol administration can alter the level of tolerance to the respiratory depressant effects of opioids - the most important physiological consequence of taking these drug in relation to death in overdose.

We will seek to elucidate at the molecular and cellular levels the signaling mechanisms underlying the development of tolerance to the respiratory depressant actions of opioid drugs and then determine how these can be affected by ethanol. Different opioid drugs are thought to induce tolerance by distinct cellular mechanisms raising the possibility that ethanol could differentially affect tolerance to different opioid drugs. For this reason we will study how tolerance develops to a range of opioids that are used illicitly and in the therapy of opioid addiction and determine the effects of acute and chronic administration of ethanol on the tolerance to each drug. We will combine whole animal studies of respiration with electrophysiological recording from neurones in the brain that control respiration and in vitro molecular studies of important mediators of opioid signaling and tolerance.

The results from our experiments will provide important new information on the dangers of the combined use of alcohol and opioids by opioid addicts and provide scientific evidence on which appropriate, important public health messages can be based.

Opioid addicts who die of acute overdose are often found to be taking other non opioid drugs as well, the most common of which is ethanol. Measurement of blood levels indicates that there is an inverse relationship between the amounts of ethanol and opioid present at death. There is to date no good, proven explanation for this relationship. We hypothesize that ethanol alters the level of opioid tolerance thus increasing the dangers for the addict to overdose even when taking their normal or even a lower dose of opioid.

To examine this hypothesis we will use a combination of experimental approaches - in vivo respiration monitoring in mice, whole cell brain cell patch clamp recording and in vitro assays of kinase and phosphatase activity- to study the interactions between ethanol and a range of opioid drugs used illicitly or in the therapy of opioid addiction. We will examine whether acute or chronic exposure to ethanol alters the level of opioid tolerance in vivo by altering the responsiveness to opioids of neurones in the brainstem that control respiration. Specifically, we will test whether acute or chronic administration of ethanol alters the levels of tolerance to each opioid drug and then use a combination of pharmacological and transgenic approaches to determine the molecular mechanisms underlying the effects observed. There is considerable evidence that different opioids induce tolerance by different molecular mechanisms and thus potentially ethanol could affect tolerance to some but not all opioid drugs.

Who will benefit?
The greatest potential impact of our work will be in informing the UK government (through the Advisory Committee on Misuse of Drugs and the Independent Scientific Committee on Drugs), healthcare policy (through the National Treatment Agency), and those in the general population who have to deal with the dangers of heroin addiction including addicts themselves.

In addition, given that we propose to extend our investigations into the potential molecular and cellular mechanisms of ethanol/opioid interactions, our research will also benefit the medical research community that have interests in the areas of pain management, respiratory pharmacology, drug tolerance and addiction. It will also inform the social science community of the biological events that may underlie epidemiological observations in the area of drug risk.

As part of his/her experience in the research project the Post Doctoral Research Assistant will be equipped with new skills and so will be able to provide essential experience for research or related jobs in academia, education, healthcare, or industry.

In more general terms our work is also of benefit to the general public in terms of our commitment to public engagement. This includes speaking in schools, and serving as scientific advisors on public bodies. Participation in these activities helps to ensure our knowledge and influence passes beyond the laboratories and walls of the University.

How will they benefit?
The dangers of alcohol consumption and heroin use are well known but what is less clear is the nature of the risk and how does it come about
- is there just simple additivity of action?
- does alcohol interact pharmacologically to reduce tolerance to heroin and increase overdose risk?
- are there situations where the same dose of ethanol can have a greater effect (e.g. when opioiod tolerance is declining in detox/incarceration)?

The National Treatment Agency policy on Drug Related Deaths demands more effective health education and interventions especially relating to the risks associated with alcohol consumption, but only by obtaining a full understanding of the processes underlying tolerance to the respiratory depressant effect of opiates and how this may be altered by ethanol, can such strategies be developed.

In summary this project will generate invaluable knowledge that will be available to those who determine healthcare policy. We will make our results freely available to the the healthcare and research communities. Data derived from the proposed research will therefore impinge on a wide and diverse array of interested parties.

The Investigators (GH & EK) will assume overall responsibility for undertaking and delivering impact activities, although it is expected that the Post Doctoral Research Assistant will make a very significant contribution as they progress through the project.

We do not anticipate any resource implications as a result of implementing the impact activities described above, which will be supported by existing funding within the University of Bristol.