GPR88 agonist(Bristol-Myers Squibb)

Hyperalgesic priming is a model system that has been widely used to understand plasticity in painful stimulus–detecting sensory neurons, called nociceptors. A key feature of this model system is that following priming, stimuli that do not normally cause hyperalgesia now readily provoke this state. We hypothesized that hyperalgesic priming occurs because of reorganization of translation of mRNA in nociceptors. To test this hypothesis, we used paclitaxel treatment as the priming stimulus and translating ribosome affinity purification to measure persistent changes in mRNA translation in Nav1.8+ nociceptors. Translating ribosome affinity purification sequencing revealed 161 genes with persistently altered mRNA translation in the primed state. Among these genes, we identified Gpr88 as upregulated and Metrn as downregulated. To provide functional evidence for these changes in hyperalgesic priming in a related priming model, we used the interleukin-6 priming model. A GPR88 agonist injection into the paw had no effect in naive mice but caused mechanical hypersensitivity and grimacing responses in female primed mice. Systemic Meteorin treatment in primed mice completely reversed established hyperalgesic priming mechanical hypersensitivity and grimacing responses to prostaglandin E2 in female mice. Our work demonstrates that altered nociceptor translatomes are causative in producing hyperalgesic priming in multiple models in female mice.