Stress Induces a Switch of Intracellular Signaling in Sensory Neurons in a Model of Generalized Pain

TLDR

Stress dramatically exacerbates pain in diseases such as fibromyalgia and rheumatoid arthritis, but the underlying mechanisms are unknown. We tested whether stress causes generalized hyperalgesia by enhancing pronociceptive effects of immune mediators. The enhancement, emerging more than a week after stress, required glucocorticoids and catecholamines acting on peripheral sensory afferent receptors. Rats exposed to nonhabituating sound stress showed no change in mechanical threshold but displayed marked hyperalgesia to prostaglandin E₂ or epinephrine, with a receptor switch from Gs to Gi and new PKCε dependence, indicating stress‑induced HPA and sympathoadrenal coactivation produces long‑lasting intracellular signaling changes that enable normally innocuous immune mediators to trigger chronic hyperalgesia.

Abstract

Stress dramatically exacerbates pain in diseases such as fibromyalgia and rheumatoid arthritis, but the underlying mechanisms are unknown. We tested the hypothesis that stress causes generalized hyperalgesia by enhancing pronociceptive effects of immune mediators. Rats exposed to nonhabituating sound stress exhibited no change in mechanical nociceptive threshold, but showed a marked increase in hyperalgesia evoked by local injections of prostaglandin E₂ or epinephrine. This enhancement, which developed more than a week after exposure to stress, required concerted action of glucocorticoids and catecholamines at receptors located in the periphery on sensory afferents. The altered response to pronociceptive mediators involved a switch in coupling of their receptors from predominantly stimulatory to inhibitory G-proteins (G_s to G_i), and for prostaglandin E₂, emergence of novel dependence on protein kinase Cε. Thus, an important mechanism in generalized pain syndromes may be stress-induced coactivation of the hypothalamo-pituitary-adrenal and sympathoadrenal axes, causing a long-lasting alteration in intracellular signaling pathways, enabling normally innocuous levels of immune mediators to produce chronic hyperalgesia.