Contributions of spinal estrogenic neurons to pain and itch
In both acute and chronic pain, females demonstrate greater sensitivity than males. One possible cause for this sex difference is a neural action of estrogen, the primary female sex hormone. To better understand the nociceptive circuits in which estrogen may act, we examined the neuronal expression of aromatase, the enzyme that catalyzes the conversion of testosterone to estrogen, in the spinal and medullary dorsal horns as well as the behavioral outcome of ablating estrogen receptor α (ERα)-expressing neurons in the superficial dorsal horn of the spinal cord. In the first study, we defined the distribution of aromatase-expressing cells in the spinal cord, caudal spinal trigeminal nucleus, and nucleus of the solitary tract in male and female aromatase reporter mice. Immunostaining for markers of neuronal subpopulations established that the aromatase-expressing cells are inhibitory interneurons that are concentrated in laminae I and V. A small percentage of these cells respond to algesic and pruritic agents.
In the second study, we determined that spinal ERα+ cells are primarily excitatory interneurons in lamina II that express the nociceptive neuropeptide substance P and receive input from myelinated primary afferents. To assess the function of the ERα-expressing neurons, we ablated these cells by injecting a Cre-dependent caspase virus into the spinal cord of both male and female ERα-Cre mice. In a battery of nociceptive and pruriceptive behavioral testing, we found that ablation reduced formalin-induced nocifensive behaviors and chloroquine-induced pruritofensive behaviors in a sexually dimorphic fashion with no impact on mechanical and thermal thresholds, capsaicin- or histamine-induced responses, or against thermal and mechanical hypersensitivity in models of chronic inflammatory and neuropathic pain. In total, we have defined two distinct populations of interneurons in the superficial dorsal horn: an inhibitory subset that can synthesize estrogen via aromatase and an excitatory subset that can respond to estrogen via ERα. These studies, although not defining the distinct contribution of estrogen to the modulation of pain and itch messages, provide evidence that these subpopulations are ideally positioned to influence pain and itch processing.