A novel functional cross-interaction between opioid and pheromone signaling may be involved in stress avoidance in Caenorhabditis elegans.

Upon sensing starvation stress, Caenorhabditis elegans larvae (L2d) elicit two seemingly opposing behaviors to escape from the stressful condition: food-seeking roaming mediated by the opioid peptide NLP-24 and dauer formation mediated by pheromones. Because opioid and pheromone signals both originate in ASI chemosensory neurons, we hypothesized that they might act sequentially or competitively to avoid starvation stress. Our data shows that NPR-17 opioid receptor signaling suppressed pheromone biosynthesis and the overexpression of opioid genes disturbed dauer formation. Likewise, DAF-37 pheromone receptor signaling negatively modulated nlp-24 expression in the ASI neurons. Under short-term starvation (STS, 3 h), both pheromone and opioid signaling were downregulated in gpa-3 mutants. Surprisingly, the gpa-3;nlp-24 double mutants exhibited much higher dauer formation than seen in either of the single mutants. Under long-term starvation (LTS, >24 h), the stress-activated SKN-1a downregulated opioid signaling and then enhanced dauer formation. Both insulin and serotonin stimulated opioid signaling, whereas NHR-69 suppressed opioid signaling. Thus, GPA-3 and SKN-1a are proposed to regulate cross-antagonistic interaction between opioids and pheromones in a cell-specific manner. These regulatory functions are suggested to be exerted via the selective interaction of GPA-3 with NPR-17 and site-specific SKN-1 binding to the promoter of nlp-24 to facilitate stress avoidance.