<i>In Vitro</i> Nociceptor Neuroplasticity Associated with <i>In Vivo</i> Opioid-Induced Hyperalgesia

Khomula, Eugen V.; Araldi, Dionéia; Levine, Jon D.

doi:10.1523/jneurosci.1191-19.2019

Cited by 26 publications

(31 citation statements)

References 105 publications

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“…Furthermore, cordycepin is described to have anti-inflammatory (reduced synovial inflammation) and analgesic effects in osteoarthritic animal models and in other conditions associated with pain and inflammation. Different mechanisms were proposed to potentially explain the effect of cordycepin on pain behaviour, such as inhibition of inflammatory signalling as well as direct effects on the primary afferent nociceptors [ 42 , 97 , 110 , 121 , 131 , 133 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 ].…”

Section: Resultsmentioning

confidence: 99%

A Systematic Review of the Biological Effects of Cordycepin

Radhi

Ashraf²,

Lawrence

et al. 2021

Molecules

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We conducted a systematic review of the literature on the effects of cordycepin on cell survival and proliferation, inflammation, signal transduction and animal models. A total of 1204 publications on cordycepin were found by the cut-off date of 1 February 2021. After application of the exclusion criteria, 791 papers remained. These were read and data on the chosen subjects were extracted. We found 192 papers on the effects of cordycepin on cell survival and proliferation and calculated a median inhibitory concentration (IC50) of 135 µM. Cordycepin consistently repressed cell migration (26 papers) and cellular inflammation (53 papers). Evaluation of 76 papers on signal transduction indicated consistently reduced PI3K/mTOR/AKT and ERK signalling and activation of AMPK. In contrast, the effects of cordycepin on the p38 and Jun kinases were variable, as were the effects on cell cycle arrest (53 papers), suggesting these are cell-specific responses. The examination of 150 animal studies indicated that purified cordycepin has many potential therapeutic effects, including the reduction of tumour growth (37 papers), repression of pain and inflammation (9 papers), protecting brain function (11 papers), improvement of respiratory and cardiac conditions (8 and 19 papers) and amelioration of metabolic disorders (8 papers). Nearly all these data are consistent with cordycepin mediating its therapeutic effects through activating AMPK, inhibiting PI3K/mTOR/AKT and repressing the inflammatory response. We conclude that cordycepin has excellent potential as a lead for drug development, especially for age-related diseases. In addition, we discuss the remaining issues around the mechanism of action, toxicity and biodistribution of cordycepin.

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Section: Resultsmentioning

confidence: 99%

A Systematic Review of the Biological Effects of Cordycepin

Radhi

Ashraf²,

Lawrence

et al. 2021

Molecules

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“…To estimate rheobase, a series of current steps with 200-pA increments was applied until APs were elicited. The protocol was then adjusted to five to six pulses with step size of 5-10% of the rheobase estimate (two to three subthreshold stimuli and two to three with AP generation, to avoid overstimulation/desensitization; Ferrari et al, 2018;Khomula et al, 2019).…”

Section: Culture Of Drg Neuronsmentioning

confidence: 99%

“…We have recently shown that m-opioid receptor (MOR) agonists, including two commonly used clinical opioids, fentanyl (Araldi et al, 2018c;Khomula et al, 2019) and morphine (Araldi et al, 2019;Ferrari et al, 2019), as well as two biased MOR agonists, PZM21 and TRV130 (Araldi et al, 2018a), can produce both OIH and opioid-induced hyperalgesic priming (OIHP). We have recently established an in vitro model of OIH, neuroplasticity induced by in vivo administration of fentanyl that persists in cultured DRG neurons, differentially affecting peptidergic and non-peptidergic nociceptors (Khomula et al, 2019). However, despite a growing literature obtained from in vivo experiments, lack of an in vitro model of OIHP has made it difficult to study underlying mechanisms at the cellular level, in identified nociceptor populations.…”

Section: Introductionmentioning

confidence: 99%

Opioid-Induced Hyperalgesic Priming in Single Nociceptors

et al. 2020

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Clinical m-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 E 2 (PGE 2 ) 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 mm) 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 2 (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 (IB41) neurons, only the response to a higher concentration of PGE 2 (100 nM) was enhanced. The sensitizing effect of 10 nM PGE 2 was attenuated in weakly IB41 and IB4-neurons cultured from rats whose OIHP was reversed in vivo. Thus, in vivo administration of fentanyl induces neuroplasticity in weakly IB41 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 PGE 2 in strongly IB41 nociceptors, not attenuated by inhibitors of Type I and Type II priming, remains to be elucidated.

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“…Culture of DRG neurons. Primary cultures of DRG neurons were made from adult male Sprague Dawley rats (weight, 220-235 g), as described previously (Ferrari et al, 2016b(Ferrari et al, , 2018Khomula et al, 2017Khomula et al, , 2019Araldi et al, 2019). In brief, under isoflurane anesthesia, rats were decapitated and the dorsum of the vertebral column surgically removed; L4 and L5 DRGs were rapidly extracted bilaterally, chilled, and desheathed in HBSS on ice.…”

Section: Methodsmentioning

confidence: 99%

Mechanisms Mediating High-Molecular-Weight Hyaluronan-Induced Antihyperalgesia

et al. 2020

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We evaluated the mechanism by which high-molecular-weight hyaluronan (HMWH) attenuates nociceptor sensitization, in the setting of inflammation. HMWH attenuated mechanical hyperalgesia induced by the inflammatory mediator prostaglandin E2 (PGE 2) in male and female rats. Intrathecal administration of an oligodeoxynucleotide antisense (AS-ODN) to mRNA for cluster of differentiation 44 (CD44), the cognate hyaluronan receptor, and intradermal administration of A5G27, a CD44 receptor antagonist, both attenuated antihyperalgesia induced by HMWH. In male rats, HMWH also signals via Toll-like receptor 4 (TLR4), and AS-ODN for TLR4 mRNA administered intrathecally, attenuated HMWH-induced antihyperalgesia. Since HMWH signaling is dependent on CD44 clustering in lipid rafts, we pretreated animals with methyl-b-cyclodextrin (MbCD), which disrupts lipid rafts. MbCD markedly attenuated HMWH-induced antihyperalgesia. Inhibitors for components of intracellular signaling pathways activated by CD44, including phospholipase C and phosphoinositide 3-kinase (PI3K), also attenuated HMWH-induced antihyperalgesia. Furthermore, in vitro application of HMWH attenuated PGE 2-induced sensitization of tetrodotoxin-resistant sodium current, in small-diameter dorsal root ganglion neurons, an effect that was attenuated by a PI3K inhibitor. Our results indicate a central role of CD44 signaling in HMWH-induced antihyperalgesia and suggest novel therapeutic targets, downstream of CD44, for the treatment of pain generated by nociceptor sensitization.

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In Vitro Nociceptor Neuroplasticity Associated with In Vivo Opioid-Induced Hyperalgesia

Cited by 26 publications

References 105 publications

A Systematic Review of the Biological Effects of Cordycepin

A Systematic Review of the Biological Effects of Cordycepin

Opioid-Induced Hyperalgesic Priming in Single Nociceptors

Mechanisms Mediating High-Molecular-Weight Hyaluronan-Induced Antihyperalgesia

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