Functional and molecular changes associated with intranasal buprenorphine in a healthy rodent model.

Abstract

Opioid addiction is a spiralling global epidemic associated with intense drug craving and the compulsive use of opiate drugs such as heroin, oxycodone, oxymorphone amongst others. Buprenorphine (BUP), commercially available as Subutex, is a partial opioid agonist that is used to treat opioid addiction and pain. It is associated with minimal risks of overdose and can be used outside of clinical care, making it the safest and most preferred choice of drug in the treatment of opioid addiction, over methadone and naltrexone. Literature suggests that opioids carry out their effects by altering the neurotransmitter systems of the brain viz. dopamine, norepinephrine, serotonin, glutamate and gamma-aminobutyric acid. Therefore, an ideal treatment drug should be able to counter these neurotransmitter changes in the brain. There is currently a lack of information on the pharmacodynamic effects of BUP in the brain, more specifically on how the drug affects brain neurotransmitter levels and its effect on the transcription factors Brain-derived neurotrophic factor (BDNF) and Cyclic AMP Response Element-Binding Protein (CREB). This study evaluates the pharmacokinetics of BUP, its effect on neurotransmitter levels and the expression of BDNF and CREB at various time points following a single dose. Sprague-Dawley rats received 36 μL of 0.3 mg/mL of BUP via intranasal administration. Following dosing, animals were euthanised and brain tissues were collected at different time points. A rapid and sensitive liquid chromatograph-mass spectrometry (LC-MS method was developed for the quantification of BUP and neurotransmitters (dopamine, serotonin, glutamate, norepinephrine and gamma-aminobutyric acid) in brain tissue and the expression of CREB and BDNF was determined using qPCR. This thesis is divided into three chapters. Chapter 1 contains a thorough background on BUP, opioid addiction and the role of neurotransmitters, BDNF and CREB. It also explains the principles of the quantification techniques used in this study i.e LC-MS and qPCR. Chapter 2 is a manuscript that was submitted to Addiction Biology titled “Functional and molecular changes associated with intranasal buprenorphine administration in a healthy rodent model”. Lastly, Chapter 3 provides a general conclusion and future recommendations for the study. The results in this present study indicate that BUP leads to significant changes in neurotransmitters, CREB and BDNF over time. Providing a better understanding of the mechanism of action of the drug, which could possibly improve the treatment of opioid addiction.