Dual Enkephalinase Inhibitor-Based Therapy in Offspring with Prenatal Fentanyl Exposure

About This Grant

PROJECT SUMMARY From 2017 to 2020, there was an alarming 5-fold increase in opioid use disorder diagnoses in pregnant women. Consequently, there is an increased number of individuals exposed to opioids during development, showing nociceptive sensitization as one common adverse health outcome. Pharmacologic management of opioid use disorder is opioid-based replacement therapy. However, there is a high demand for testing of non-opioid-based therapies to apply during developmental and early life. Neonatal opioid withdrawal symptoms are characterized by nociceptive sensitization. To move forward with the development of interventions to mitigate the effects of opioid withdrawal in neonates with prenatal fentanyl exposure (PFE), we subjected pregnant rats to fentanyl self-administration during preconception and gestation. Our preliminary data show that neonates with PFE displayed reduced cephalic index, higher rates of low birth weight, and somatic signs of withdrawal compared with vehicle-exposed offspring, which mirrors several pregnancy outcomes associated with opioid use disorder. Our data indicates that weanlings with PFE showed reduced latency of nociception evoked by the hot plate test, a thermal stimulus involving supraspinal integration. When offspring with PFE reached adulthood, they showed chronic sympathetic activation and exacerbated fentanyl-induced tolerance and hyperalgesia in response to fentanyl re-exposure. Enkephalins are endogenous ligands that bind with higher affinity to ä-OR than ì-OR, mediating pain sensitivity and somatic symptoms during withdrawal. ä-ORs are found in both noradrenergic dendrites and glial cells of locus coeruleus (LC), the primary site for brain norepinephrine synthesis and release in the brainstem. Enkephalins can reduce the release of norepinephrine and the duration of action potentials in LC-noradrenergic neurons, playing a pivotal role in thermal pain sensitivity associated with opioid withdrawal. In humans, dual ENKephalinase inhibitors (DENKi) are promising medications for neurogenic pain that avoid the breakdown of endogenous enkephalins by extracellular metalloproteases neprilysin and aminopeptidase A. Notably, PFE reduced [met]-enkephalin levels in the brainstem and hypothalamus from weanlings, whereas the levels of this opioid peptide in LC remained lower in adult life. The central hypothesis is that preventing the degradation of endogenous opioid peptides in offspring with PFE may increase enkephalins half-life, precluding the overactivation of LC-noradrenergic neurons, and reducing opioid-induced hyperalgesia in neonatal and adult offspring. We will investigate whether 1) increasing enkephalin dampens the activity of LC-noradrenergic neurons, reducing neonatal opioid withdrawal and hyperalgesia in offspring with PFE, and 2) whether increasing enkephalin half-life in adult offspring with prenatal fentanyl exposure diminishes opioid-induced tolerance and hyperalgesia by activating ä-OR in LC.