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Neurosci."],"published-print":{"date-parts":[[2021,1,6]]},"abstract":"<jats:p>Clinical \u00b5-opioid receptor (MOR) agonists produce hyperalgesic priming, a form of maladaptive nociceptor neuroplasticity, resulting in pain chronification. We have established an<jats:italic>in vitro<\/jats:italic>model of opioid-induced hyperalgesic priming (OIHP), in male rats, to identify nociceptor populations involved and its maintenance mechanisms. OIHP was induced<jats:italic>in vivo<\/jats:italic>by systemic administration of fentanyl and confirmed by prolongation of prostaglandin E<jats:sub>2<\/jats:sub>(PGE<jats:sub>2<\/jats:sub>) hyperalgesia. Intrathecal cordycepin, which reverses Type I priming, or the combination of Src and mitogen-activated protein kinase (MAPK) inhibitors, which reverses Type II priming, both partially attenuated OIHP. Parallel<jats:italic>in vitro<\/jats:italic>experiments were performed on small-diameter (&lt;30 \u00b5m) dorsal root ganglion (DRG) neurons, cultured from fentanyl-primed rats, and rats with OIHP treated with agents that reverse Type I or Type II priming. Enhancement of the sensitizing effect of a low concentration of PGE<jats:sub>2<\/jats:sub>(10 n<jats:sc>m<\/jats:sc>), another characteristic feature of priming, measured as reduction in action potential (AP) rheobase, was found in weakly isolectin B4 (IB4)-positive and IB4-negative (IB4\u2013) neurons. In strongly IB4-positive (IB4+) neurons, only the response to a higher concentration of PGE<jats:sub>2<\/jats:sub>(100 n<jats:sc>m<\/jats:sc>) was enhanced. The sensitizing effect of 10 n<jats:sc>m<\/jats:sc>PGE<jats:sub>2<\/jats:sub>was attenuated in weakly IB4+ and IB4\u2013 neurons cultured from rats whose OIHP was reversed<jats:italic>in vivo<\/jats:italic>. Thus,<jats:italic>in vivo<\/jats:italic>administration of fentanyl induces neuroplasticity in weakly IB4+ and IB4\u2013 nociceptors that persists<jats:italic>in vitro<\/jats:italic>and has properties of Type I and Type II priming. The mechanism underlying the enhanced sensitizing effect of 100 n<jats:sc>m<\/jats:sc>PGE<jats:sub>2<\/jats:sub>in strongly IB4+ nociceptors, not attenuated by inhibitors of Type I and Type II priming, remains to be elucidated.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>Commonly used clinical opioid analgesics, such as fentanyl and morphine, can produce hyperalgesia and chronification of pain. To uncover the nociceptor population mediating opioid-induced hyperalgesic priming (OIHP), a model of pain chronification, and elucidate its underlying mechanism, at the cellular level, we established an<jats:italic>in vitro<\/jats:italic>model of OIHP. In dorsal root ganglion (DRG) neurons cultured from rats primed with fentanyl, robust nociceptor population-specific changes in sensitization by prostaglandin E<jats:sub>2<\/jats:sub>(PGE<jats:sub>2<\/jats:sub>) were observed, when compared with nociceptors from opioid naive rats. In DRG neurons cultured from rats with OIHP, enhanced PGE<jats:sub>2<\/jats:sub>-induced sensitization was observed<jats:italic>in vitro<\/jats:italic>, with differences identified in non-peptidergic [strongly isolectin B4 (IB4)-positive] and peptidergic [weakly IB4-positive (IB4+) and IB4-negative (IB4\u2013)] nociceptors.<\/jats:p>","DOI":"10.1523\/jneurosci.2160-20.2020","type":"journal-article","created":{"date-parts":[[2020,11,17]],"date-time":"2020-11-17T23:06:09Z","timestamp":1605654369000},"page":"31-46","source":"Crossref","is-referenced-by-count":24,"title":["Opioid-Induced Hyperalgesic Priming in Single Nociceptors"],"prefix":"10.1523","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0221-2237","authenticated-orcid":false,"given":"Eugen V.","family":"Khomula","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8379-2901","authenticated-orcid":false,"given":"Dion\u00e9ia","family":"Araldi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6008-3237","authenticated-orcid":false,"given":"Ivan J. 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