Unpredictable sound stress induces a novel form of hyperalgesic priming

Unpredictable stress induces long-lasting nociceptor plasticity, enhancing and prolonging pain, contributing to chronic pain. To enhance our understanding of how unpredictable stress induces pronociceptive neuroplasticity, we investigated its effect on nociceptor function, testing the hypothesis that unpredictable sound stress (SS) induces hyperalgesic priming, a model of acute to chronic pain transition. Male rats were subjected to intense amplitude (20-110 dB) unpredictable sound, 5- or 10-second tones presented every minute, at random times, for 30 minutes, on days 1, 3, and 4. On day 18, prostaglandin E2 (PGE2) was administered intradermally. In both sham and SS groups, PGE2 induces hyperalgesia, measured at 30 minutes postinjection. However, only in the SS group was PGE2 hyperalgesia still present at 4 hours, indicative of hyperalgesic priming. Agents known to inhibit the expression and maintenance of type I priming, inhibitors of protein kinase C epsilon, and peripheral protein translation, respectively, did not affect the SS-induced prolongation of PGE2-induced hyperalgesia. In contrast, a protein kinase A (PKA) inhibitor attenuated the prolongation of PGE2-induced hyperalgesia. This inhibition remained, unattenuated, when evaluated 1 month after administration of the PKA inhibitor, compatible with PKA contributing to both expression and maintenance of SS-induced hyperalgesic priming. The effect of combined Src and mitogen-activated protein kinase inhibitors, which fully reverses type II priming, also inhibited SS-induced priming; however, this effect diminished over time. Our findings support a novel form of hyperalgesic priming induced by SS. Insights into the mechanisms underlying SS-induced priming could inform targeted interventions for pain syndromes influenced by stress.