Cannabidiol and Cannabigerol, Nonpsychotropic Cannabinoids, as Analgesics that Effectively Manage Bone Fracture Pain and Promote Healing in Mice

Deepak Kumar Khajuria, Vengadeshprabhu Karuppagounder, Irena Nowak, Diana E. Sepulveda, Gregory S. Lewis, Christopher C. Norbury, Wesley M. Raup-Konsavage, Kent E. Vrana, Fadia Kamal, Reyad A. Elbarbary

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Bone fractures are among the most prevalent musculoskeletal injuries, and pain management is an essential part of fracture treatment. Fractures heal through an early inflammatory phase, followed by repair and remodeling. Nonsteroidal anti-inflammatory drugs (NSAIDs) are not recommended for fracture pain control as they potently inhibit the inflammatory phase and, thus, impair the healing. Opioids do not provide a better alternative for several reasons, including abuse potential. Accordingly, there is an unmet clinical need for analgesics that effectively ameliorate postfracture pain without impeding the healing. Here, we investigated the analgesic efficacy of two nonpsychotropic cannabinoids, cannabidiol (CBD) and cannabigerol (CBG), in a mouse model for tibial fracture. Mice with fractured tibiae exhibited increased sensitivity to mechanical, cold, and hot stimuli. Both CBD and CBG normalized pain sensitivity to all tested stimuli, and their analgesic effects were comparable to those of the NSAIDs. Interestingly, CBD and CBG promoted bone healing via multiple mechanisms during the early and late phases. During the early inflammatory phase, both cannabinoids increased the abundance of periosteal bone progenitors in the healing hematoma and promoted the osteogenic commitment of these progenitors. During the later phases of healing, CBD and CBG accelerated the fibrocartilaginous callus mineralization and enhanced the viability and proliferation of bone and bone-marrow cells. These effects culminated in higher bone volume fraction, higher bone mineral density, and improved mechanical quality of the newly formed bone. Together, our data suggest CBD and CBG as therapeutic agents that can replace NSAIDs in managing postfracture pain as both cannabinoids exert potent analgesic effects and, at the same time, promote bone healing.

Original languageEnglish
Pages (from-to)1560-1576
Number of pages17
JournalJournal of Bone and Mineral Research
Volume38
Issue number11
Early online date19 Aug 2023
DOIs
StatePublished - Nov 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Funding

Analysis of the plasma concentrations of CBD and CBG was performed at the Mass Spectrometry Core Facility (small molecules) (RRID no. is SCR_017831), and the FC analysis was performed at the Flow Cytometry and Cell Sorting core (RRID no. SCR_021134) at the Penn State University College of Medicine. Kent E. Vrana (and the Penn State College of Medicine) is the recipient of research support from PA Options for Wellness (a state-approved medical marijuana clinical registrant). The funding sources were not involved in study design, providing any experimental materials, data collection, data analysis and interpretation, writing of the report, or the decision to submit the article for publication. The authors would like to acknowledge members of the state-approved medical marijuana academic clinical research center at Penn State for insights and comments on the data and study design. This work was supported by National Institutes of Health (NIH) grants R01 DK121327 to Reyad A. Elbarbary and R01 AR071968 to Fadia Kamal. Analysis of the plasma concentrations of CBD and CBG was performed at the Mass Spectrometry Core Facility (small molecules) (RRID no. is SCR_017831), and the FC analysis was performed at the Flow Cytometry and Cell Sorting core (RRID no. SCR_021134) at the Penn State University College of Medicine. Kent E. Vrana (and the Penn State College of Medicine) is the recipient of research support from PA Options for Wellness (a state‐approved medical marijuana clinical registrant). The funding sources were not involved in study design, providing any experimental materials, data collection, data analysis and interpretation, writing of the report, or the decision to submit the article for publication. The authors would like to acknowledge members of the state‐approved medical marijuana academic clinical research center at Penn State for insights and comments on the data and study design. This work was supported by National Institutes of Health (NIH) grants R01 DK121327 to Reyad A. Elbarbary and R01 AR071968 to Fadia Kamal.

FundersFunder number
Mass Spectrometry Core FacilitySCR_017831, SCR_021134
PA Options for Wellness
Penn State University College of Medicine
National Institutes of HealthR01 DK121327, R01 AR071968
Penn State College of Medicine

    Keywords

    • ANALGESIC
    • BONE REGENERATION
    • CANNABIDIOL
    • CANNABIGEROL
    • FRACTURE HEALING

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