Characterization Of Decursinol Efficacy, Tolerance, And Mechanism In Models Of Pain
Restricted (Penn State Only)
- Author:
- Crawford, Lataijah
- Graduate Program:
- Biomedical Sciences (PHD)
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- July 07, 2023
- Committee Members:
- Junxuan Lu, Outside Field Member
Patricia Grigson Kennedy, Outside Unit Member
Ralph Keil, Program Head/Chair
John Ellis, Major Field Member
Daniel Morgan, Special Member
Lisa Shantz, Chair & Dissertation Advisor - Keywords:
- AGN; Angelica gigas Nakai
DOH; Decursinol
CENP; Chemotherapy-evoked neuropathic pain
MOR; Morphine
NXO; Naloxone
TRPA1; Transient receptor potential ankyrin 1
TRPV1
Transient receptor vanilloid receptor 1
TRPV1; Transient receptor vanilloid receptor 1
5-HT2; Serotonin receptor 2
5-HT2A; Serotonin receptor 2A
5-HT2C; Serotonin receptor 2C
CB1; Cannabinoid receptor type 1
CB2; Cannabinoid receptor type 2
WT; Wild-type mouse - Abstract:
- Previous studies have shown that oral administration of Angelica gigas Nakai (AGN) root alcoholic extract and decursinol, the metabolite of its pyranocoumarins, decursin and decursinol angelate, have antinociceptive properties across various acute thermal and inflammatory pain models. The objectives of this study were to: 1) assess whether tolerance develops to the antinociceptive effects of once-daily intraperitoneally administered decursinol in acute thermal pain and persistent pain models; 2) establish its anti-allodynic efficacy and potential tolerance development in a model of chemotherapy-evoked neuropathic (CENP) pain; and 3) probe the involvement of select receptors in mediating the pain-relieving effects of decursinol. Here we have demonstrated that intraperitoneally administered decursinol induced antinociceptive effects in the hot plate, tail-flick, and formalin tests in addition to a reversal of mechanical allodynia in CENP mice. Although there are few reports comparing the anti-inflammatory properties of decursinol to the commonly prescribed non-steroidal anti-inflammatory agents (NSAIDs), we established in the current work that decursinol was roughly 3-fold less potent than the classic opioid morphine in both the formalin test and in CENP mice. Our study was the first to report evidence of tolerance development to the antinociceptive effects of decursinol in the acute thermal pain models using wild-type (WT) mice and to the anti-allodynic effects of decursinol in neuropathic mice, at a pace slower than that reported for morphine. We report for the first-time hypothermia and sedation/ataxia effects of decursinol to partially overlap and confound the pain-relieving efficacy assessment. Previous literature alluded to the potential involvement of serotonergic, histamine, adenosine A2, and noradrenergic receptor signaling in the mediation of the reported antinociceptive effects of orally administered decursinol. However, pretreatment with either the 5-HT2 receptor antagonist, Methysergide, the 5-HT2A antagonist, Volinanserin, or the 5-HT2C antagonist, SB-242084, failed to attenuate decursinol-induced antinociception in the tail-flick assay. Nevertheless, the antinocifensive effects of decursinol might involve CB1, NXO, and TRPA1 signaling in the formalin-induced inflammatory pain model. Along with assessing the anti-allodynic effects of decursinol in neuropathic mice. We have shown using the cisplatin-evoked neuropathic mice, that pretreatment with the cannabinoid inverse agonists, Rimonabant and SR144528, both failed to attenuate the decursinol-induced anti-allodynic effects. Contrary to the evidence previously reported of the lack of opioid receptor signaling involvement in decursinol-induced antinociception in WT mice, we have shown that pretreatment with the opioid antagonist, naloxone partially attenuated the anti-allodynic effects of decursinol. In conclusion, our data supports decursinol as an active phytochemical from AGN having both antinociceptive and anti-allodynic properties. Future work warrants an investigation of potential receptor mechanisms including the opioid receptor and TRPA1 signaling in persistent and neuropathic pain models, as the potential mechanism(s) is likely more complicated than initially reported.