NKTR-181: A Novel Mu-Opioid Analgesic with Inherently Low Abuse Potential.

The increasing availability of prescription opioid analgesics for the treatment of pain has been paralleled by an epidemic of opioid misuse, diversion, and overdose. The development of abuse-deterrent formulations (ADFs) of conventional opioids such as oxycodone and morphine represents an advance in the field and has had a positive but insufficient impact, as most opioids are still prescribed in highly abusable, non-ADF forms, and abusers can tamper with ADF medications to liberate the abusable opioid within. The abuse liability of mu-opioid agonists appears to be dependent on their rapid rate of entry into the central nervous system (CNS), whereas analgesic activity appears to be a function of CNS exposure alone, suggesting that a new opioid agonist with an inherently low rate of influx across the blood-brain barrier could mediate analgesia with low abuse liability, regardless of formulation or route of administration. NKTR-181 is a novel, long-acting, selective mu-opioid agonist with structural properties that reduce its rate of entry across the blood-brain barrier compared with traditional mu-opioid agonists. NKTR-181 demonstrated maximum analgesic activity comparable to that of oxycodone in hot-plate latency and acetic-acid writhing models. NKTR-181 was distinguishable from oxycodone by its reduced abuse potential in self-administration and progressive-ratio break point models, with behavioral effects similar to those of saline, as well as reduced CNS side effects as measured by the modified Irwin test. The in vitro and in vivo studies presented here demonstrate that NKTR-181 is the first selective mu-opioid agonist to combine analgesic efficacy and reduced abuse liability through the alteration of brain-entry kinetics.

Moderate fetal alcohol exposure impairs the neurogenic response to an enriched environment in adult mice.

BACKGROUND: Prenatal ethanol exposure results in a spectrum of cognitive and behavioral deficits and affects an estimated thirteen percent of children born in the United States. The basis of prenatal ethanol-induced impairment of brain function has been widely studied in animal models, where significant changes in the physiological and structural plasticity of hippocampal function have been documented. Here, we explored the possibility that exposure to moderate levels of alcohol in utero might also result in long-lasting impairment of adult hippocampal neurogenesis, a novel form of plasticity that occurs throughout adulthood. METHODS: Female mice were trained to voluntarily consume 10% EtOH throughout pregnancy using the two-bottle choice paradigm, which results in moderate blood alcohol levels of approximately 121 mg/dl, as previously described (Allan et al., 2003). Offspring were exposed to standard or enriched living conditions for 8-12 weeks post-weaning. BrdU was administered at 50 mg/kg for 12 consecutive days. Mice in each housing condition were sacrificed at either 24 hrs or four weeks following the final BrdU injection, and BrdU cells within the dentate gyrus were evaluated using immuno-histochemical methods. RESULTS: Neither fetal alcohol exposure (FAE) nor enriched environment affected the number of proliferating progenitors within the subgranular zone (SGZ) of the dentate gyrus. However, FAE severely impaired the neurogenic response to enriched environment. Control mice housed in enriched environment displayed a two-fold increase in hippocampal neurogenesis, whereas FAE mice responded to enriched environment with neither enhanced progenitor survival nor enhanced neuronal differentiation. CONCLUSIONS: These observations indicate that moderate FAE results in a long-term, persistent defect in neurogenic responses to behavioral challenge.