Delta Opioid Receptor-Mediated Antidepressant-Like Effects of Diprenorphine in Mice

Abstract

Major depressive disorder is a highly common disorder, with a lifetime prevalence in the USA of approximately 21 %. Traditional antidepressant treatments are limited by a delayed onset of action and minimal efficacy in some patients. Ketamine is effective and fast-acting, but there are concerns over its abuse liability. Thus, there is a need for safe, fast acting antidepressant drugs. The opioid buprenorphine shows promise but also has abuse liability due to its mu-agonist component. Preclinical evidence indicates that the delta-opioid system contributes to mood disorders and delta opioid agonists are effective in preclinical models of depression-and anxiety-like states. In this study we test the hypothesis that the mu-opioid antagonist diprenorphine by virtue of its partial delta opioid agonist activity may offer a beneficial profile for an antidepressant medication without abuse liability. Diprenorphine was confirmed to bind with high affinity to all three opioid receptors, and functional experiments for G protein activation verified diprenorphine to be a partial agonist at delta-and kappa-opioid receptors and a mu-antagonist. Studies in C57BL/6 mice demonstrated that an acute dose of diprenorphine produced antidepressant-like effects in the tail suspension test and the novelty-induced hypophagia test that were inhibited in the presence of the delta-selective antagonist, naltrindole. Diprenorphine did not produce convulsions, a side-effect of many delta agonists, but rather inhibited convulsions caused by the full delta agonist SNC80; however, diprenorphine did potentiate pentylenetetrazole-induced convulsions.Diprenorphine, and compounds with a similar pharmacological profile, may provide for efficient and safe rapidly acting antidepressants.

The Impact of UFP-512 in Mice with Osteoarthritis Pain: The Role of Hydrogen Sulfide

“…The opioid system plays a pivotal function in pain management. Previous findings have demonstrated the analgesic effects of µ-(MOR), δ-(DOR) and/or k-opioid receptor agonists [6][7][8][9] and their involvement in the control of affective disorders [10][11][12][13]. MOR are the main target of opioids, but morphine and other MOR agonists also have important side…”

“…DORs are fully distributed in the peripheral nervous system (PNS) and in several brain regions, including the amygdala (AMG), cortex, hippocampus (HIP) and periaqueductal gray matter [12,19]. In fact, DORs additionally modulated the emotional responses in several preclinical models of depression and anxiety [13] as well as in mice with depressive-like behaviors concurrent with neuropathic pain [20]. However, the effects of DOR agonists on pain relief and on the modulation of the functional and affective deficits related to OA pain have not been completely explored.…”