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Research Articles, Cellular/Molecular

Opioid-Induced Hyperalgesic Priming in Single Nociceptors

Eugen V. Khomula, Dionéia Araldi, Ivan J. M. Bonet and Jon D. Levine
Journal of Neuroscience 6 January 2021, 41 (1) 31-46; DOI: https://doi.org/10.1523/JNEUROSCI.2160-20.2020
Eugen V. Khomula
Departments of Medicine and Oral and Maxillofacial Surgery, Division of Neuroscience, and UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, California 94143
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Dionéia Araldi
Departments of Medicine and Oral and Maxillofacial Surgery, Division of Neuroscience, and UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, California 94143
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Ivan J. M. Bonet
Departments of Medicine and Oral and Maxillofacial Surgery, Division of Neuroscience, and UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, California 94143
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Jon D. Levine
Departments of Medicine and Oral and Maxillofacial Surgery, Division of Neuroscience, and UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, California 94143
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Abstract

Clinical µ-opioid receptor (MOR) agonists produce hyperalgesic priming, a form of maladaptive nociceptor neuroplasticity, resulting in pain chronification. We have established an in vitro model of opioid-induced hyperalgesic priming (OIHP), in male rats, to identify nociceptor populations involved and its maintenance mechanisms. OIHP was induced in vivo by systemic administration of fentanyl and confirmed by prolongation of prostaglandin E2 (PGE2) 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 in vitro experiments were performed on small-diameter (<30 µm) 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 PGE2 (10 nm), 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–) neurons. In strongly IB4-positive (IB4+) neurons, only the response to a higher concentration of PGE2 (100 nm) was enhanced. The sensitizing effect of 10 nm PGE2 was attenuated in weakly IB4+ and IB4– neurons cultured from rats whose OIHP was reversed in vivo. Thus, in vivo administration of fentanyl induces neuroplasticity in weakly IB4+ and IB4– nociceptors that persists in vitro and has properties of Type I and Type II priming. The mechanism underlying the enhanced sensitizing effect of 100 nm PGE2 in strongly IB4+ nociceptors, not attenuated by inhibitors of Type I and Type II priming, remains to be elucidated.

SIGNIFICANCE STATEMENT 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 in vitro model of OIHP. In dorsal root ganglion (DRG) neurons cultured from rats primed with fentanyl, robust nociceptor population-specific changes in sensitization by prostaglandin E2 (PGE2) were observed, when compared with nociceptors from opioid naive rats. In DRG neurons cultured from rats with OIHP, enhanced PGE2-induced sensitization was observed in vitro, with differences identified in non-peptidergic [strongly isolectin B4 (IB4)-positive] and peptidergic [weakly IB4-positive (IB4+) and IB4-negative (IB4–)] nociceptors.

  • excitability
  • fentanyl
  • isolectin B4
  • neuroplasticity
  • nociceptor
  • sensitization

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The Journal of Neuroscience: 41 (1)
Journal of Neuroscience
Vol. 41, Issue 1
6 Jan 2021
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Opioid-Induced Hyperalgesic Priming in Single Nociceptors
Eugen V. Khomula, Dionéia Araldi, Ivan J. M. Bonet, Jon D. Levine
Journal of Neuroscience 6 January 2021, 41 (1) 31-46; DOI: 10.1523/JNEUROSCI.2160-20.2020

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Opioid-Induced Hyperalgesic Priming in Single Nociceptors
Eugen V. Khomula, Dionéia Araldi, Ivan J. M. Bonet, Jon D. Levine
Journal of Neuroscience 6 January 2021, 41 (1) 31-46; DOI: 10.1523/JNEUROSCI.2160-20.2020
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Keywords

  • excitability
  • fentanyl
  • isolectin B4
  • neuroplasticity
  • nociceptor
  • sensitization

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