Fentanyl-induced antinociception, reward, reinforcement, and withdrawal in Hnrnph1 mutant mice

Opioid Use Disorder (OUD) and opioid-related deaths remain a major public health concern in the United States. Both environmental and genetic factors influence risk for OUD. We previously identified as a quantitative trait gene underlying the stimulant, rewarding, and reinforcing properties of methamphetamine. Prior work demonstrates that hnRNP H1, the RNA-binding protein encoded by post-transcriptionally regulates (mu opioid receptor gene) – the primary molecular target for the therapeutic and addictive properties of opioids. Because genetic variants can exert pleiotropic effects on behaviors induced by multiple drugs of abuse, in the current study, we tested the hypothesis that mutants would show reduced behavioral sensitivity to the mu opioid receptor agonist fentanyl. mutants showed reduced sensitivity to fentanyl-induced locomotor activity, along with a female-specific reduction in, and a male-specific induction of, locomotor sensitization following three, daily injections (0.2 mg/kg, i.p.). mutants also required a higher dose of fentanyl to exhibit opioid reward as measured via conditioned place preference. Male mutants showed reduced fentanyl reinforcement. mutants also showed reduced sucrose motivation, suggesting a reward deficit. No genotypic differences were observed in baseline thermal nociception, fentanyl-induced antinociception, physical or negative affective signs of opioid dependence, or in sensorimotor gating. In the context of our prior work, these findings suggest that dysfunction exerts a selective role in reducing the addiction liability to drugs of abuse (opioids and psychostimulants), which could provide new biological pathways to improve their therapeutic profiles.