Identifying novel targets in opioid addiction: Pre-clinical and clinical studies
Opioid dependence affects nearly 1% of the world's population and is a devastating global health problem without an effective curative treatment. As opioid dependence prevalence and mortality rates escalate, it is imperative that current recovery paradigms are optimized while simultaneous novel pharmacological interventions are explored. To do so necessitates an enhanced understanding of both individuals vulnerable to relapse and novel neuroanatomical targets that regulate opioids. Ideal screening for drop-out prone individuals seeking opioid dependence treatment would be at intake due to the rapid drop off of compliant patients over the course of the first year of treatment. The clinical studies undertaken in this dissertation aimed to assess whether stress reactivity is a risk-factor for premature treatment discontinuation. Stress reactivity was assessed via perceived stress and post-traumatic stress disorder symptomatology at admission: creating a stress reactivity index (SRI). While stabilization on a constant dose of methadone in combination with continued opioid-free urine drug screens significantly predicted survival out to three months, the SRI, in addition to drug severity indices, served as earlier proxy measures. Together these assessments accounted for 13-30% of the variance across outcome measures with higher stress reactivity predicting inconsistent group therapy attendance, ongoing opioid use, poor stabilization, and fewer days until drop-out. Considering the strong impact of stress on recovery the preclinical studies were targeted in the rat locus coeruleus (LC)-norepinephrine (NE) system where environmental, emotional, and physical stress afferents converge on opioid sensitive addiction-related pathways. Within such neurons, adaptations in cell signaling cascades develop following opioid actions at the mu opioid receptor (MOR) and molecular and cellular adaptations to morphine exposure have been well characterized. Morphine has been shown to induce a re-distribution of Wntless (WLS), a MOR-interacting protein (MORIP), from cytoplasmic to membrane compartments in rat striatal neurons providing some insight into the mechanism of action of opioids. The co-localization of WLS and MOR specifically in the LC was confirmed via western blot analysis, in addition to immunocytochemistry with confocal microscopy that suggested a high rate of somatodendritic overlap of both proteins. Rats received saline, morphine or the opiate agonist [D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO), followed by sequential high resolution single and dual immunogold-silver electron microscopy that revealed a significant re-distribution of WLS to the plasma membrane, often in close proximity to MOR, following morphine treatment. The differential nature of addictive morphine-like substances and potential role of subsequent trafficking differences was implied by contrasting DAMGO treatment, where MOR and WLS were predominantly localized within the cytoplasmic compartment of the neurons. These findings allow future work to build upon the therapeutic potential of MORIPs, like WLS, and may lead to a pharmacological adjunct for stress-vulnerable individuals entering opioid replacement therapy that could prevent relapse and improve overall treatment of opioid dependence.
Jaremko, Kellie Marie, "Identifying novel targets in opioid addiction: Pre-clinical and clinical studies" (2013). ETD Collection for Thomas Jefferson University. AAI3613204.