Dynorphin and Enkephalin Opioid Peptides and Transcripts in Spinal Cord and Dorsal Root Ganglion During Peripheral Inflammatory Hyperalgesia and Allodynia |
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| Affiliation: | 2. National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland;3. Flow and Imaging Cytometry Core Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland;2. University of Texas Health Science Center San Antonio, San Antonio, Texas;3. VA Greater Los Angeles Health Care System, Los Angeles, California;4. David Geffen School of Medicine at UCLA, Los Angeles, California;6. VA Salt Lake City Health Care System, Salt Lake City, Utah;5. University of Utah School of Medicine, Salt Lake City, Utah;2. Institute for Musculoskeletal Health, Sydney, New South Wales, Australia;3. Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway;4. Clinic of Anesthesia and Intensive Care, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway;5. Discipline of Physiotherapy, Faculty of Health Sciences, The University of Sydney, Sydney, New South Wales, Australia;2. War Related Illness and Injury Study Center, Veterans Affairs New Jersey Healthcare System, East Orange, New Jersey;3. University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;4. Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania;2. Department of Chemistry, Drug Discovery Division, Southern Research Institute, Birmingham, Alabama |
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| Abstract: | Understanding molecular alterations associated with peripheral inflammation is a critical factor in selectively controlling acute and persistent pain. The present report employs in situ hybridization of the 2 opioid precursor mRNAs coupled with quantitative measurements of 2 peptides derived from the prodynorphin and proenkephalin precursor proteins: dynorphin A 1-8 and [Met5]-enkephalin-Arg6-Gly7-Leu8. In dorsal spinal cord ipsilateral to the inflammation, dynorphin A 1-8 was elevated after inflammation, and persisted as long as the inflammation was sustained. Qualitative identification by high performance liquid chromatography and gel permeation chromatography revealed the major immunoreactive species in control and inflamed extracts to be dynorphin A 1-8. In situ hybridization in spinal cord after administration of the inflammatory agent, carrageenan, showed increased expression of prodynorphin (Pdyn) mRNA somatotopically in medial superficial dorsal horn neurons. The fold increase in preproenkephalin mRNA (Penk) was comparatively lower, although the basal expression is substantially higher than Pdyn. While Pdyn is not expressed in the dorsal root ganglion (DRG) in basal conditions, it can be induced by nerve injury, but not by inflammation alone. A bioinformatic meta-analysis of multiple nerve injury datasets confirmed Pdyn upregulation in DRG across different nerve injury models. These data support the idea that activation of endogenous opioids, notably dynorphin, is a dynamic indicator of persistent pain states in spinal cord and of nerve injury in DRG.PerspectiveThis is a systematic, quantitative assessment of dynorphin and enkephalin peptides and mRNA in dorsal spinal cord and DRG neurons in response to peripheral inflammation and axotomy. These studies form the foundational framework for understanding how endogenous spinal opioid peptides are involved in nociceptive circuit modulation. |
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