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. 2022 Sep 29:13:968976.
doi: 10.3389/fphar.2022.968976. eCollection 2022.

Decursinol-mediated antinociception and anti-allodynia in acute and neuropathic pain models in male mice: Tolerance and receptor profiling

LaTaijah C Crawford  1   2 , Sangyub Kim  3 , Deepkamal Karelia  3 , Diana E Sepulveda  3 , Daniel J Morgan  2 , Junxuan Lü  1   3 , Angela N Henderson-Redmond  2
Affiliations

Decursinol-mediated antinociception and anti-allodynia in acute and neuropathic pain models in male mice: Tolerance and receptor profiling

LaTaijah C Crawford et al. Front Pharmacol. .

Abstract

Korean scientists have shown that oral administration of Angelica gigas Nakai (AGN) root alcoholic extract and the metabolite of its pyranocoumarins, decursinol, have antinociceptive properties across various thermal and acute inflammatory pain models. The objectives of this study were 1) to assess whether tolerance develops to the antinociceptive effects of once-daily intraperitoneally administered decursinol (50 mg/kg) in acute thermal pain models, 2) to establish its anti-allodynic efficacy and potential tolerance development in a model of chemotherapy-evoked neuropathic pain (CENP) and 3) to probe the involvement of select receptors in mediating the pain-relieving effects with antagonists. The results show that decursinol induced antinociception in both the hot plate and tail-flick assays and reversed mechanical allodynia in mice with cisplatin-evoked neuropathic pain. Tolerance was detected to the antinociceptive effects of decursinol in the hot plate and tail-flick assays and to the anti-allodynic effects of decursinol in neuropathic mice. Pretreatment with either the 5-HT2 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. While pretreatment with the cannabinoid inverse agonists rimonabant and SR144528 failed to modify decursinol-induced anti-allodynia, pretreatment with the opioid antagonist naloxone partially attenuated the anti-allodynic effects of decursinol. In conclusion, our data support decursinol as an active phytochemical of AGN having both antinociceptive and anti-allodynic properties. Future work warrants a more critical investigation of potential receptor mechanisms as they are likely more complicated than initially reported.

Keywords: antinociception; decursinol; mice; neuropathic pain; tolerance.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Chemical structures of morphine and the non-opioid alternative, decursinol. Chemical structures of AGN root signature pyranocoumarins in alcoholic extracts and their relationship in AGN plant phytochemical syntheses (Green arrow) vs. in mammalian pharmacology drug metabolism (Red arrow).
FIGURE 2
FIGURE 2
Decursinol-induced antinociception and hypothermia. Cumulative dose-response curves were generated using male mice (N = 12) to assess the antinociceptive and hypothermic effects of vehicle (VEH), 10, 30, 50, and 70 mg/kg decursinol in the hot plate (A), tail-flick (B), and hypothermia (C) assays. Mice were injected with increasing doses of decursinol and assessed for antinociception (%MPE) and hypothermia (%ΔBT) 30 min later. Error bars represent the mean ± SEM. Data were analyzed using repeated measures (RM) one-way ANOVAs and Bonferroni post hoc tests. (****p < 0.0001 compared to VEH).
FIGURE 3
FIGURE 3
Development of antinociceptive (but not hypothermic) tolerance to once-daily 50 mg/kg of decursinol. Tolerance to the antinociceptive and hypothermic effects of 50 mg/kg of decursinol (filled circles; N = 12) or vehicle (unfilled circles; N = 12) was examined in male mice. Mice were assessed for antinociception via the hot plate (A) and tail-flick (B) assays and for hypothermia (C) following treatment with either decursinol or vehicle (VEH). Data are expressed as mean ± SEM and were analyzed using a two-way ANOVA with Bonferroni post-hoc tests. (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 compared to VEH).
FIGURE 4
FIGURE 4
Serotonin Receptor 2 (5-HT2) signaling does not attenuate decursinol-induced antinociception or hypothermia. Mediation of the acute antinociceptive (A/B) and hypothermic (C) effects of 50 mg/kg decursinol by 5-HT 2 antagonists in male mice. Mice (N = 10) were assessed for hot plate (A) and tail-flick (B) antinociception (%MPE) and hypothermia (C; %ΔBT) 30 min following pretreatment with either vehicle (VEH), 4 mg/kg of the non-selective 5-HT2 antagonist Methysergide (MS), 4 mg/kg of the selective 5-HT2A antagonist Volinanserin (5-HT2A), or 4 mg/kg of the selective 5-HT2C receptor antagonist SB-242084 (5-HT2C) and again 30 min following treatment with either vehicle (VEH; unfilled bars) or 50 mg/kg of decursinol (DOH; filled bars). Error bars represents the mean ± SEM. Data were analyzed using a repeated measures one-way ANOVA with Bonferroni post-hoc tests (***p < 0.001; ****p < 0.0001 compared to VEH/VEH; # p < 0.05 compared to VEH/DOH).
FIGURE 5
FIGURE 5
Decursinol dose-dependently reverses cisplatin-induced mechanical allodynia in neuropathic male mice. Dose-response curves were generated using male mice to assess the anti-allodynic effects of decursinol in mice with cisplatin-induced neuropathy. Mice were assessed via the von Frey for the amount of force (in grams) required to elicit a paw withdrawal response prior to cisplatin treatment (Pre BL), following cisplatin-evoked neuropathy (Post BL), and 30 min following treatment with either vehicle (0) and 1, 3, 10, 30, and 50 mg/kg decursinol (DOH; N = 30). Error bars represents the mean ± SEM. Each mouse was tested in triplicate per dose, and these values were averaged into a single value per mouse per day of testing. Data were analyzed using a repeated-measures one-way ANOVA with Bonferroni post-hoc tests. (****p < 0.001 compared to 0).
FIGURE 6
FIGURE 6
Development of tolerance to the anti-allodynic and hypothermic effects of once-daily administration of 50 mg/kg decursinol in neuropathic mice. Tolerance to the anti-allodynic (A) and hypothermic (B) effects of decursinol in neuropathic mice was assessed 30 min following once-daily administration of either vehicle (open squares; N = 16) or 50 mg/kg of decursinol (filled squares; N = 16). Mice were assessed for the amount of force (in grams) required to elicit a paw withdrawal response (30 min) and body temperature (40 min) following treatment with either decursinol (DOH; 50 mg/kg) or vehicle (VEH). Error bars represents the mean ± SEM. Each moue was tested in triplicate and those values averaged into a single value per mouse per day of treatment. Data were analyzed using a two-way ANOVA with Bonferroni post-hoc tests (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001; ^p < 0.05 compared to Day 1 of DOH treatment indicative of the first day of partial tolerance development).
FIGURE 7
FIGURE 7
Cannabinoid and opioid mediation of the anti-allodynic and hypothermic effects of decursinol in mice with cisplatin-induced neuropathy. Mediation of the anti-allodynic (A) and hypothermic (B) effects of 50 mg/kg decursinol by CB1, CB2, and/or opioid receptors in male mice (N = 13). Mice were assessed via the von Frey for the amount of force (in grams) required to elicit a paw withdrawal response prior to cisplatin treatment (Pre BL) and following cisplatin-evoked neuropathy (Post BL). Mice were also assessed for the ability of the CB1 inverse agonist Rimonabant (CB1A), the CB2 inverse agonist SR144528 (CB2A), and the nonselective opioid antagonist naloxone (NXO) to mediate the anti-allodynic effects of 50 mg/kg of decursinol by administering either 10 mg/kg of CB1A or CB2A, 10 mg/kg of NXO, or vehicle (VEH) 30 min prior to treatment with either decursinol (DOH) or vehicle (VEH). For each mouse, testing occurred in triplicate per mouse and was averaged into a single value per mouse per day of testing. Error bars represents the mean ± SEM. Data were analyzed using a repeated measures one-way ANOVA with Bonferroni post-hoc tests (**p < 0.01,****p < 0.0001 compared to VEH/VEH; # p < 0.05 compared to VEH/DOH; $ p < 0.0001 Pre versus Post BL).
FIGURE 8
FIGURE 8
Decursinol-induced ataxia in male mice. Mice were assessed for the ataxic effects of decursinol (A) across a range of doses and tolerance to both the ataxic (B) and hypothermic (C) effects of decursinol to dissociate confounds of ataxia on tolerance to the antinociceptive effects of decursinol on tail-flick (D). Using an accelerating rotarod, mice were assessed for the mean latency (in seconds) to fall 30 min post decursinol administration on the rotarod across dose (A) or on days 1, 7, and 14 across 14 days of once-daily administration of 50 mg/kg decursinol (N = 8; red bars) or vehicle (VEH; N = 2; white bars). Mice were also assessed for tolerance to hypothermia on days 1, 7, and 14 of decursinol administration (C) and on Day 15 to see if mice were tolerant to the antinociceptive effects of decursinol following 14 days of once-daily administration on the tail-flick. Error bars represents the mean ± SEM and data were analyzed using a repeated measure one-way (A) or two-way (B,C) ANOVA with Bonferroni post-hoc tests (*p < 0.05, ****p < 0.0001 compared to Veh) or a t-test (D).
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