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We therefore hypothesized that selectively stimulating LC neurons would reduce nociception after TBI. All experiments used a well-characterized rat lateral fluid percussion model of TBI. NA neurons were stimulated by administering clozapine N-oxide (CNO) to rats selectively expressing a designer receptor exclusively activated by designer drug (DREADD) viral construct in their LC's. Mechanical nociceptive thresholds were measured using von Frey fibers. The efficacy of diffuse noxious inhibitory control (DNIC), a critical endogenous pain control mechanism, was assessed using the hindpaw administration of capsaicin. Immunohistochemical analyses demonstrated the selective expression of the DREADD construct in LC neurons after stereotactic injection. During the 1st week after TBI, when rats demonstrated hindlimb (HL) nociceptive sensitization, CNO administration provided transient anti-allodynia in DREADD-expressing rats but not in rats injected with control virus. Seven weeks after TBI we observed a complete loss of DNIC in response to capsaicin. However, CNO administration largely restored DNIC in TBI DREADD-expressing rats but not those injected with control virus. Unexpectedly, the effects of LC activation in the DREADD-expressing rats were blocked by the \u03b1-1 adrenergic receptor antagonist prazosin, but not the \u03b1-2 adrenergic receptor antagonist atipamezole. These results suggest that directly stimulating the LC after TBI can reduce both early and late manifestations of dysfunctional endogenous pain regulation. Clinical approaches to activating descending pain circuits may reduce suffering in those with pain after TBI.<\/jats:p>","DOI":"10.1089\/neu.2021.0485","type":"journal-article","created":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T12:52:01Z","timestamp":1649767921000},"page":"964-978","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":8,"title":["Activation of the Locus Coeruleus Mediated by Designer Receptor Exclusively Activated by Designer Drug Restores Descending Nociceptive Inhibition after Traumatic Brain Injury in Rats"],"prefix":"10.1177","volume":"39","author":[{"given":"Karen-Amanda","family":"Irvine","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Perioperative and Pain Medicine; Stanford University, School of Medicine, Stanford, California, USA."},{"name":"Anesthesiology Service; Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Peters","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena M.","family":"Vazey","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Massachusetts Amherst, Amherst Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam R.","family":"Ferguson","sequence":"additional","affiliation":[{"name":"University of California San Francisco, Brain and Spinal Injury Center, Department of Neurosurgery, San Francisco, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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