Date of Award
1-1-2025
Document Type
Dissertation
Degree Name
Ph.D. in Pharmaceutical Sciences
First Advisor
Nicole M. Ashpole
Second Advisor
John Rimoldi
Third Advisor
Noa Valcarcel
School
University of Mississippi
Relational Format
dissertation/thesis
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating adverse symptom experienced in over 60% of patients receiving chemotherapy treatment. Unfortunately, current therapeutic strategies require long-term treatment with limited efficacy, often requiring opioid-based medications. To mitigate the adverse effects of current therapeutics, studies suggest cannabis-based medicines to alleviate neuroinflammation and related pain. Multiple studies have explored Δ9-tetrahydrocannabinol and synthetic cannabinoids, however, an ideal cannabinoid candidate for drug development would be devoid of psychoactive effects. Our current study evaluates the effectiveness of cannabichromene (CBC), shown to have anti-inflammatory properties and devoid of psychoactive effects, on alleviating chemotherapy-induced neuropathic pain (CIPN) by assessing both behavioral responses to pain and the underlying cellular and molecular mechanisms by which CBC enacts its effects.
A series of behavioral, mechanistic, and pharmacokinetic studies were conducted to evaluate the therapeutic potential of cannabichromene (CBC) and its derivative, CBC-Val-Hs, in chemotherapy-induced peripheral neuropathy (CIPN) models. Behavioral assessments of CIPN were conducted using an electronic von Frey to measure mechanical sensitivity in mice subjected to vincristine, oxaliplatin, cisplatin, or paclitaxel dosing regimens. The efficacy of CBC was compared to current CIPN therapeutics, with additional analyses evaluating drug duration effects and the potential for CIPN prevention. Mechanistic studies were conducted to investigate the involvement of the antioxidant, oxidative stress, and inflammatory signaling in mediating the antinociceptive effects of CBC. Finally, improving the efficacy of CBC through structural modification was evaluated by pharmacokinetic analyses following oral and intravenous administration in mice, with serum concentrations quantified to assess bioavailability and metabolic stability.
Behavioral assessments demonstrated that acute CBC administration effectively attenuated cisplatin-IPN. However, co-administration of CBC with cisplatin did not prevent cisplatin-IPN onset. Comparisons with existing CIPN therapeutics showed that the antinociceptive effects of CBC were comparable to duloxetine but with potential advantages in the duration of relief. Mechanistic studies indicated that these antinociceptive properties were not dependent on modulating oxidative stress or inflammatory signaling pathways. Pharmacokinetic analysis revealed that CBC-Val-Hs exhibited greater bioavailability than CBC, with higher serum concentrations following oral and intravenous administration. CBC-Val-Hs maintained the antinociceptive effects of CBC, supporting its potential as a more bioavailable therapeutic candidate for CIPN.
These data indicate that CBC can delay the onset of cisplatin-induced neuropathic pain, supporting its potential as a novel therapeutic for alleviating CIPN. However, the mechanisms underlying the protective effects of CBC remain unclear and require further investigation. Given that CBC-Val-Hs exhibits greater bioavailability than CBC, it may serve as a more effective therapeutic candidate. Future studies will examine the role of CBC in mitochondrial bioenergetics and further delineate the mechanisms by which CBC and CBC-Val-Hs exert their antinociceptive effects.
Recommended Citation
De Leon, Miguel Antonio, "Examining the Effects of the Minor Cannabinoid Cannabichromene (CBC) on Chemotherapy-Induced Peripheral Neuropathy: Behavioral and Molecular Insights" (2025). Electronic Theses and Dissertations. 3266.
https://egrove.olemiss.edu/etd/3266