{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:13:39Z","timestamp":1791299619125,"version":"4.1.0"},"reference-count":47,"publisher":"National Academy of Sciences","issue":"14","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1999,7,6]]},"abstract":"<jats:p>Compelling evidence has accumulated over the last several\n years from our laboratory, as well as others, indicating that central\n hyperactive states resulting from neuronal plastic changes within the\n spinal cord play a critical role in hyperalgesia associated with nerve\n injury and inflammation. In our laboratory, chronic constriction injury\n of the common sciatic nerve, a rat model of neuropathic pain, has been\n shown to result in activation of central nervous system excitatory\n amino acid receptors and subsequent intracellular cascades including\n protein kinase C translocation and activation, nitric oxide production,\n and nitric oxide-activated poly(ADP ribose) synthetase activation.\n Similar cellular mechanisms also have been implicated in the\n development of tolerance to the analgesic effects of morphine. A\n recently observed phenomenon, the development of \u201cdark neurons,\u201d\n is associated with both chronic constriction injury and morphine\n tolerance. A site of action involved in both hyperalgesia and morphine\n tolerance is in the superficial laminae of the spinal cord dorsal horn.\n These observations suggest that hyperalgesia and morphine tolerance may\n be interrelated at the level of the superficial laminae of the dorsal\n horn by common neural substrates that interact at the level of\n excitatory amino acid receptor activation and subsequent intracellular\n events. The demonstration of interrelationships between neural\n mechanisms underlying hyperalgesia and morphine tolerance may lead to a\n better understanding of the neurobiology of these two phenomena in\n particular and pain in general. This knowledge may also provide a\n scientific basis for improved pain management with opiate analgesics.<\/jats:p>","DOI":"10.1073\/pnas.96.14.7731","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:38:21Z","timestamp":1027679901000},"page":"7731-7736","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":348,"title":["Cellular mechanisms of neuropathic pain, morphine tolerance, and their interactions"],"prefix":"10.1073","volume":"96","author":[{"given":"David J.","family":"Mayer","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Medical College of Virginia,\r Virginia Commonwealth University, Richmond, VA 23298;\r Department of Cell Biology, Duke University School of Medicine,\r Durham, NC 27710; and Departments of Oral Surgery and\r Neuroscience, University of Florida, Gainesville, FL 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