Alterations in neurotransmitter levels and transcription factor expression following intranasal buprenorphine administration

• Published in: Biomedicine & pharmacotherapy Vol. 138; p. 111515
• Main Authors: Xhakaza, Sanelisiwe P., Khoza, Leon J., Haripershad, Advaitaa M., Ghazi, Terisha, Dhani, Shanel, Mutsimhu, Cosmas, Molopa, Molopa J., Madurai, Nithia P., Madurai, Lorna, Singh, Sanil D., Gopal, Nirmala D., Kruger, Hendrik G., Govender, Thavendran, Chuturgoon, Anil, Naicker, Tricia, Baijnath, Sooraj
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.06.2021; Elsevier
• Subjects: Administration, Intranasal - methods; Analgesics, Opioid - administration & dosage; Animals; Brain - drug effects; Brain - metabolism; Brain-derived neurotrophic factor (BDNF); Brain-Derived Neurotrophic Factor - biosynthesis; Brain-Derived Neurotrophic Factor - genetics; Buprenorphine; Buprenorphine - administration & dosage; Cyclic AMP response element-binding protein (CREB); Cyclic AMP Response Element-Binding Protein - biosynthesis; Cyclic AMP Response Element-Binding Protein - genetics; Gene Expression; Male; Neurotransmitter Agents - biosynthesis; Neurotransmitter Agents - genetics; Neurotransmitters; Opioid addiction; Rats; Rats, Sprague-Dawley; Transcription Factors - biosynthesis; Transcription Factors - genetics; Opioid addiction; Neurotransmitters; Buprenorphine; Brain-derived neurotrophic factor (BDNF); Cyclic AMP response element-binding protein (CREB)
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2021.111515

Buprenorphine is an opioid drug used in the management of pain and the treatment opioid addiction. Like other opioids, it is believed that it achieves these effects by altering functional neurotransmitter pathways and the expression of important transcription factors; cyclic AMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in the brain. However, there is a lack of scientific evidence to support these theories. This study investigated the pharmacodynamic effects of BUP administration by assessing neurotransmitter and molecular changes in the healthy rodent brain. Sprague-Dawley rats (150–200 g) were intranasally administered buprenorphine (0.3 mg/mL) and sacrificed at different time points: 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h post drug administration. LC-MS was used to quantify BUP and neurotransmitters (GABA, GLUT, DA, NE and 5-HT) in the brain, while CREB and BDNF gene expression was determined using qPCR. Results showed that BUP reached a Cmax of 1.21 ± 0.0523 ng/mL after 2 h, with all neurotransmitters showing an increase in their concentration over time, with GABA, GLUT and NE reaching their maximum concentration after 8 h. DA and 5-HT reached their maximum concentrations at 1 h and 24 h, respectively post drug administration. Treatment with BUP resulted in significant upregulation in BDNF expression throughout the treatment period while CREB showed patterns of significant upregulation at 2 and 8 h, and downregulation at 1 and 6 h. This study contributes to the understanding of the pharmacodynamic effects of BUP in opioid addiction by proving that the drug significantly influences NT pathways that are implicated in opioid addiction. •The pharmacokinetics of BUP and its effects on neurotransmitters and the expression of CREB and BDNF were investigated.•BUP reached a Cmax 2 h post BUP administration with GABA, GLUT and NE reaching their maximum concentrations after 8 h.•DA and 5-HT peaked at 1 h and 8 h post-dose, respectively.•BUP significantly increased the expression of BDNF throughout the treatment period, while CREB showed variable expression.