Journal article
Opioid-Induced Hyperalgesic Priming in Single Nociceptors
The Journal of neuroscience, Vol.41(1), pp.31-46
01/06/2021
DOI: 10.1523/JNEUROSCI.2160-20.2020
PMID: 33203743
Abstract
Clinical µ-opioid receptor (MOR) agonists produce hyperalgesic priming, a form of maladaptive nociceptor neuroplasticity, resulting in pain chronification. We have established an
model of opioid-induced hyperalgesic priming (OIHP), in male rats, to identify nociceptor populations involved and its maintenance mechanisms. OIHP was induced
by systemic administration of fentanyl and confirmed by prolongation of prostaglandin E
(PGE
) 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
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 PGE
(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 PGE
(100 nm) was enhanced. The sensitizing effect of 10 nm PGE
was attenuated in weakly IB4+ and IB4- neurons cultured from rats whose OIHP was reversed
Thus,
administration of fentanyl induces neuroplasticity in weakly IB4+ and IB4- nociceptors that persists
and has properties of Type I and Type II priming. The mechanism underlying the enhanced sensitizing effect of 100 nm PGE
in strongly IB4+ nociceptors, not attenuated by inhibitors of Type I and Type II priming, remains to be elucidated.
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
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
(PGE
) were observed, when compared with nociceptors from opioid naive rats. In DRG neurons cultured from rats with OIHP, enhanced PGE
-induced sensitization was observed
, with differences identified in non-peptidergic [strongly isolectin B4 (IB4)-positive] and peptidergic [weakly IB4-positive (IB4+) and IB4-negative (IB4-)] nociceptors.
Details
- Title: Subtitle
- Opioid-Induced Hyperalgesic Priming in Single Nociceptors
- Creators
- Eugen V Khomula - University of California, San FranciscoDionéia Araldi - University of California, San FranciscoIvan J M Bonet - University of California, San FranciscoJon D Levine - University of California, San Francisco
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.41(1), pp.31-46
- DOI
- 10.1523/JNEUROSCI.2160-20.2020
- PMID
- 33203743
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Language
- English
- Date published
- 01/06/2021
- Academic Unit
- Neuroscience and Pharmacology
- Record Identifier
- 9985178669202771
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