Morphine-Induced Antinociception Is Potentiated and Dopamine Elevations Are Inhibited by the Biased Kappa Opioid Receptor Agonist Triazole 1.1

Traditional analgesic opioid compounds, which act through mu opioid receptors (MORs), engender a high risk for misuse and dependence. kappa opioid receptor (KOR) activation, a potential target for pain treatment, produces antinociception without euphoric side effects but results in dysphoria and aversion. Triazole 1.1 is a KOR agonist biased toward G-protein coupled signaling, potentially promoting antinociception without dysphoria. We tested whether triazole 1.1 could provide antinociception and its effects in combination with morphine. We employed a lactic acid abdominal pain model, which induced acute pain behaviors, decreased basal dopamine levels in the nucleus accumbens (NAc), and increased KOR function. We administered several interventions including triazole 1.1 (30 mg/kg) and morphine (12 or 24 mg/kg), individually and in combination. Triazole 1.1 alone reduced the pain behavioral response and changes to KOR function but did not prevent the reduction in basal dopamine levels. Morphine not only dose-dependently prevented behavioral pain responses but also elevated NAc dopamine and did not prevent the pain-induced increase in KOR function. However, combining low-dose morphine with triazole 1.1 prevents behavioral pain responses, changes to NAc dopamine levels, and changes to KOR function. Therefore, we present triazole 1.1 as a dose-sparing pain treatment to be used in combination with a lower dose of morphine, thus reducing the potential for opioid misuse.