Highlights
- •We present the molecular response in dorsal spinal cord to peripheral inflammation.
- •Identify ALK as an induced neuronal tyrosine kinase receptor in dynorphinergic neurons.
- •Distinguish interferon immune responses from afferent driven complement increase.
- •Identify targetable analgesic signaling molecules induced by peripheral injury.
- •Articulate application of RNA-Seq to analgesic drug discovery.
Abstract
During persistent pain, the dorsal spinal cord responds to painful inputs from the
site of injury, but the molecular modulatory processes have not been comprehensively
examined. Using transcriptomics and multiplex in situ hybridization, we identified
the most highly regulated receptors and signaling molecules in rat dorsal spinal cord
in peripheral inflammatory and post-surgical incisional pain models. We examined a
time course of the response including acute (2 hours) and longer term (2 day) time
points after peripheral injury representing the early onset and instantiation of hyperalgesic
processes. From this analysis, we identify a key population of superficial dorsal
spinal cord neurons marked by somatotopic upregulation of the opioid neuropeptide
precursor prodynorphin, and 2 receptors: the neurokinin 1 receptor, and anaplastic
lymphoma kinase. These alterations occur specifically in the glutamatergic subpopulation
of superficial dynorphinergic neurons. In addition to specific neuronal gene regulation,
both models showed induction of broad transcriptional signatures for tissue remodeling,
synaptic rearrangement, and immune signaling defined by complement and interferon
induction. These signatures were predominantly induced ipsilateral to tissue injury,
implying linkage to primary afferent drive. We present a comprehensive set of gene
regulatory events across 2 models that can be targeted for the development of non-opioid
analgesics.
Perspective
The deadly impact of the opioid crisis and the need to replace morphine and other
opioids in clinical practice is well recognized. Embedded within this research is
an overarching goal of obtaining foundational knowledge from transcriptomics to search
for non-opioid analgesic targets. Developing such analgesics would address unmet clinical
needs.
Key Words
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Article info
Publication history
Published online: April 20, 2021
Accepted:
March 16,
2021
Received in revised form:
March 12,
2021
Received:
October 29,
2020
Footnotes
DISCLOSURES: This work was supported by the Intramural Reseach Programs of the Clinical Center, the National Institute of Neurological Disorders and Stroke and the National Institutes of Nursing Research, National Institutes of Health. This work was also supported by funds from the National Center for Complementary and Integrative Health (1ZIAAT000017-03), and the Office of Behavioral and Social Sciences Research. TG was supported by the Japan Society for the Promotion of Science Overseas Research Fellowship. Funding for two research fellows (J.J.K. and F.A.V.), was made possible through the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation (DDCF Grant #2014194), the American Association for Dental Research, the Colgate-Palmolive Company, Genentech, Elsevier, and other private donors.
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© Published by Elsevier Inc. on behalf of United States Association for the Study of Pain, Inc.
