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Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2017)

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.

    Cover page: Contributions of spinal estrogenic neurons to pain and itch
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2017)
    In both acute and chronic pain conditions, women tend to be more sensitive than men. This sex difference may be regulated by estrogens, such as estradiol, that are synthesized in the spinal cord and brainstem and act locally to influence pain processing. To identify a potential cellular source of local estrogen, here we examined the expression of aromatase, the enzyme that catalyzes the conversion of testosterone to estradiol. Our studies focused on primary afferent neurons and on their central targets in the spinal cord and medulla as well as in the nucleus of the solitary tract, the target of nodose ganglion-derived visceral afferents. Immunohistochemical staining in an aromatase reporter mouse revealed that many neurons in laminae I and V of the spinal cord dorsal horn and caudal spinal trigeminal nucleus and in the nucleus of the solitary tract express aromatase. The great majority of these cells also express inhibitory interneuron markers. We did not find sex differences in aromatase expression and neither the pattern nor the number of neurons changed in a sciatic nerve transection model of neuropathic pain or in the Complete Freund's adjuvant model of inflammatory pain. A few aromatase neurons express Fos after cheek injection of capsaicin, formalin, or chloroquine. In total, given their location, these aromatase neurons are poised to engage nociceptive circuits, whether it is through local estrogen synthesis or inhibitory neurotransmitter release.
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2017)
      In both acute and chronic pain conditions, women tend to be more sensitive than men. This sex difference may be regulated by estrogens, such as estradiol, that are synthesized in the spinal cord and brainstem and act locally to influence pain processing. To identify a potential cellular source of local estrogen, here we examined the expression of aromatase, the enzyme that catalyzes the conversion of testosterone to estradiol. Our studies focused on primary afferent neurons and on their central targets in the spinal cord and medulla as well as in the nucleus of the solitary tract, the target of nodose ganglion-derived visceral afferents. Immunohistochemical staining in an aromatase reporter mouse revealed that many neurons in laminae I and V of the spinal cord dorsal horn and caudal spinal trigeminal nucleus and in the nucleus of the solitary tract express aromatase. The great majority of these cells also express inhibitory interneuron markers. We did not find sex differences in aromatase expression and neither the pattern nor the number of neurons changed in a sciatic nerve transection model of neuropathic pain or in the Complete Freunds adjuvant model of inflammatory pain. A few aromatase neurons express Fos after cheek injection of capsaicin, formalin, or chloroquine. In total, given their location, these aromatase neurons are poised to engage nociceptive circuits, whether it is through local estrogen synthesis or inhibitory neurotransmitter release.
        Cover page: Neuronal aromatase expression in pain processing regions of the medullary and spinal cord dorsal horn.
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2020)
        Estrogens are presumed to underlie, at least in part, the greater pain sensitivity and chronic pain prevalence that women experience compared to men. Although previous studies revealed populations of estrogen receptor-expressing neurons in primary afferents and in superficial dorsal horn neurons, there is little to no information as to the contribution of these neurons to the generation of acute and chronic pain. Here we molecularly characterized neurons in the mouse superficial spinal cord dorsal horn that express estrogen receptor α (ERα) and explored the behavioral consequences of their ablation. We found that spinal ERα-positive neurons are largely excitatory interneurons and many coexpress substance P, a marker for a discrete subset of nociceptive, excitatory interneurons. After viral, caspase-mediated ablation of spinal ERα-expressing cells, we observed a significant decrease in the first phase of the formalin test, but in male mice only. ERα-expressing neuron-ablation also reduced pruritogen-induced scratching in both male and female mice. There were no ablation-related changes in mechanical or heat withdrawal thresholds or in capsaicin-induced nocifensive behavior. In chronic pain models, we found no change in Complete Freund's adjuvant-induced thermal or mechanical hypersensitivity, or in partial sciatic nerve injury-induced mechanical allodynia. We conclude that ERα labels a subpopulation of excitatory interneurons that are specifically involved in chemically evoked persistent pain and pruritogen-induced itch.
          Cover page: Ablation of spinal cord estrogen receptor α‐expressing interneurons reduces chemically induced modalities of pain and itch
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