Administration of a Biased Kappa Opioid Receptor Agonist as a Non-addictive Analgesic in Mice

Poster Title: Administration of a biased kappa opioid receptor agonist as a non-addictive analgesic in mice

Student: Tallia Pearson, Class of 2024

Faculty Mentor and Department: Sara Jones Physiology and Pharmacology

Funding Source:  NIH/NIDA R01 DA048490; Department of Physiology and Pharmacology, Wake Forest School of Medicine

ABSTRACT

Background: Morphine activates the mu opioid receptor, which provides desired effects such as analgesia, but also leads to detrimental, undesired effects such as misuse, development of addiction, and overdose liability, primarily through its dopamine-elevating properties. Another class of opioid receptors, kappa opioid receptors (KORs), when activated provide analgesic effects without abuse potential, making the KOR a potential therapeutic target for non-addictive pain medications. However, most KOR agonists are aversive due to negative emotional effects, making them less attractive for clinical use. Recently, a new category of non-aversive, “biased” KOR agonists has been suggested for analgesia, but their potential for producing addiction on their own and possible interactions with mu agonists such as morphine have not been explored.

Hypothesis: Because addictive effects of morphine involve increasing dopamine levels in the nucleus accumbens, and pain is known to decrease dopamine levels, we will test the hypothesis that a biased KOR agonist, Triazole 1.1, will exert dopamine-normalizing effects and block both pain-induced reductions and morphine-induced increases in dopamine levels within the nucleus accumbens.

Methods: Dopamine levels in the nucleus accumbens were measured via microdialysis subsequent to administration of the biased kappa opioid receptor (KOR) agonist Triazole 1.1, alone and in combination with acute morphine, in mice experiencing pain induced by intraperitoneal administration of lactic acid.

Results: Triazole 1.1 prevented the decrease of dopamine levels in the nucleus accumbens associated with mild pain induced by ip injections of lactic acid and blocked the typical increase in dopamine levels induced by morphine.

Conclusions: These findings suggest future use of Triazole 1.1 in combination opioid analgesic treatment to work towards a method of analgesic medication without addictive properties. Such a treatment is particularly important as it could aid thousands of people suffering from chronic pain and work towards combatting the opioid epidemic.

Source of mentor’s funding or other support that funded this research: 

National Institutes of Health, National Institute on Drug Abuse grant R01 DA048490-01 (Sara Jones, PI)

“Biased Kappa Opioid Agonists as Non-addictive Analgesics”