Evaluating the anti-nociceptive efficacy of cannabidiol (CBD) alone or in combination with morphine using the formalin test in male and female mice

Phytocannabinoids have emerged as a potential alternative treatment option for individuals experiencing persistent pain. However, evidence-based research regarding their clinical utility in both males and females remains incomplete. Additionally, it is unknown whether combining readily available cannabinoids with opioids has a synergistic or sub-additive effect on pain modulation. To begin to fill this knowledge gap, we investigated the anti-nociceptive effects of the phytocannabinoid, cannabidiol (CBD), either alone or in combination with opioids in male and female C57BL/6J mice. Employing the formalin test, our results show that CBD (10 mg/kg, i.p.) treatment evoked anti-nociception in phase I, but not in phase II of the formalin test in male mice. However, in female mice, CBD showed no significant anti-nociceptive effect. Additionally, a direct sex comparison showed that CBD evoked a significant increase in nociceptive behaviors in female versus male mice during phase I of the formalin test. Furthermore, we show that CBD (10 mg/kg, i.p.) in combination with low-dose morphine (1 mg/kg, i.p.) was ineffective at eliciting a synergistic anti-nociceptive response in both male and female mice. Lastly, consistent with previous literature, we showed that females treated with a relatively higher dose of morphine (10 mg/kg, i.p.) displayed a significant increase in the variability of nociceptive behaviors compared to morphine-treated male mice. Overall, our results suggest that CBD treatment may have beneficial anti-nociceptive effects during the acute phase of persistent pain, but these effects are more beneficial to males than females. In conclusion, we provide further preclinical support that treatments geared toward reducing nociceptive behaviors differentially affect males and females.

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Work Title Evaluating the anti-nociceptive efficacy of cannabidiol (CBD) alone or in combination with morphine using the formalin test in male and female mice
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Open Access
Creators
  1. Diana Sepulveda
  2. Daniel Morris
  3. Wesley Raup-Konsavage
  4. Dongxiao Sun
  5. Kent E. Vrana
  6. Nicholas Graziane
Keyword
  1. Cannabinoids
  2. Formalin assay
  3. CBD
  4. Male and female mice
  5. Pain
License In Copyright (Rights Reserved)
Work Type Article
Publication Date October 2022
Deposited March 21, 2023

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Version 1
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  • Created
  • Updated
  • Added Creator Diana Sepulveda
  • Added Creator Daniel Morris
  • Added Creator Wesley Raup-Konsavage
  • Added Creator Dongxiao Sun
  • Added Creator Kent E. Vrana
  • Added Creator Nicholas Graziane
  • Added 2021-Sepulveda-CBD Paper-V5-corrections accepted.docx
  • Updated License Show Changes
    License
    • https://rightsstatements.org/page/InC/1.0/
  • Published
  • Updated Work Title, Publisher, Publisher Identifier (DOI) Show Changes
    Work Title
    • Evaluating the anti-nociceptive efficacy of cannabidiol (CBD) alone or in combination with morphine using the formalin test in male and female mice.
    • Evaluating the antinociceptive efficacy of cannabidiol (CBD) alone or in combination with morphine using the formalin test in male and female mice
    Publisher
    • Cannabis and Cannabinoid Research
    Publisher Identifier (DOI)
    • https://doi.org/10.1089/can.2021.0108
  • Updated Keyword Show Changes
    Keyword
    • cannabinoids, formalin assay, CBD, male and female mice, pain
  • Updated Work Title, Keyword, Publisher, and 1 more Show Changes
    Work Title
    • Evaluating the antinociceptive efficacy of cannabidiol (CBD) alone or in combination with morphine using the formalin test in male and female mice
    • Evaluating the anti-nociceptive efficacy of cannabidiol (CBD) alone or in combination with morphine using the formalin test in male and female mice
    Keyword
    • cannabinoids, formalin assay, CBD, male and female mice, pain
    • Cannabinoids, Formalin assay, CBD, Male and female mice, Pain
    Publisher
    • Cannabis and Cannabinoid Research
    Publisher Identifier (DOI)
    • https://doi.org/10.1089/can.2021.0108
  • Updated