Background & Aims
Patients and physicians have become increasingly interested in reducing the number of pain medications prescribed in recent years. Between the opioid crisis, the gastrointestinal (GI) side effects of most NSAIDs, and the current scrutiny of gabapentinoids, it is becoming increasingly clear that the long-term use of these molecules is not harmless. To reduce their use, we must provide adjuvant supportive therapies to maintain patient satisfaction with pain management. The public and researchers are turning their attention to cannabis products. Cannabidiol (CBD) has shown promising analgesic capacity in human and rodent pain models[1] and is safer in terms of cognitive side effects.
This study examines the analgesic effect of a CBD-aloe vera formulation, which increases the bioavailability of CBD, on rodent preclinical models of visceral and neuropathic pain, as well as on the excitability of human sensory neurons.
Methods
Animals: 8 wk-old male and female C57BL/6 mice (Charles River Labs); with N=4-6 per group.
Treatment: Two treatments per day (morning and evening, 250 µL, i.p) with a vehicle (0.1% DMSO in saline), aloe vera alone (12 mg/mL), or in combination with Cannabidiol (CBD, 2 mg/mL). Both products were provided by Desert Harvest©.
Pain Model: Discomfort was assessed in murine models of visceral pain (cystitis, induced by a single injection of cyclophosphamide (CYP, 400 mg/kg, intraperitoneally, n=6 per group)), neuropathic pain (Chronic Constriction Injury (CCI), and Taxol (10 mg/kg on Days 0, 2, 4, and 6)).
Pain Test: Different aspects of discomfort were evaluated. Tactile (von Frey) and cold (acetone test) sensitivity were measured on the plantar surface of the foot (CCI, Taxol) or supra-pelvic region (CYP). Pain scores, body weight, and urination were also monitored for CYP mice, as previously described[4].
Human neurons: neurons were plated and recorded as shown previously [5].
Results
Aloes/CBD and Cystitis:
After a single dose of cyclophosphamide, tactile hypersensitivity develops rapidly in the supra-pelvic region, reaching a maximum allodynia 24h post-CYP, which persists for 48h. However, spontaneous behavioral signs of discomfort peaked at 4h post-CYP and gradually resolved within 48h. While none of the treatments affected the time course of tactile sensitivity, the CBD-Aloe Vera formulation significantly reduced the severity of the discomfort peak (pain score).
CBD/aloe and Neuropathic pain:
On D13, 2 weeks after nerve ligation (CCI) or chemotherapy (Taxol), all mice showed a significant reduction in their 50% withdrawal threshold (von Frey test) and a sustained nocifensive response to acetone application, indicating the presence of mechanical and cold allodynia, respectively. After 7 days of treatment (twice daily, D14-20), only mice exposed to the CBD/aloe combination showed reduced mechanical but not cold allodynia.
Excitability of human neurons:
Overnight incubation of human neurons with the CBD/aloe led to a decrease in electrical excitability demonstrated by a reduced input-output curve. Other aspects such as cell capacitance, resting membrane voltage, action potential threshold and rheobase remained unchanged.
Conclusions
Administering low-dose CBD twice daily shows promise as an effective adjunctive treatment for comprehensive pain management, owing to its significant therapeutic benefits coupled with a minimal side effect profile. This regimen notably mitigates the initial peak of discomfort typically observed in the early stages of cystitis and alleviates mechanical allodynia in neuropathic conditions resulting from chemotherapy or traumatic nerve injuries in mice. Implementing routine low doses of CBD may also contribute to reducing reliance on opioids and gabapentinoids.
Future research should focus on assessing the efficacy of CBD, both as a standalone treatment and in combination with other therapies, in attenuating spontaneous pain behaviors, such as weight-bearing difficulties in Chronic Constriction Injury (CCI) models.
References
1.Britch, S.C., S. Babalonis, and S.L. Walsh, Cannabidiol: pharmacology and therapeutic targets. Psychopharmacology (Berl), 2021. 238(1): p. 9-28.
2.Austin, P.J., A. Wu, and G. Moalem-Taylor, Chronic constriction of the sciatic nerve and pain hypersensitivity testing in rats. J Vis Exp, 2012(61).
3.Smith, S.B., S.E. Crager, and J.S. Mogil, Paclitaxel-induced neuropathic hypersensitivity in mice: responses in 10 inbred mouse strains. Life Sci, 2004. 74(21): p. 2593-604.
4.Leventhal, L. and B. Strassle, A model of cystitis pain in the mouse. Curr Protoc Pharmacol, 2008. Chapter 5: p. Unit 5 52.
5. Mouchbahani-Constance S, Lagard C, Schweizer J, Labonté I, Georgiopoulos M, Otis C, St-Louis M, Troncy E, Sarret P, Ribeiro-Da-Silva A, Ouellet JA, Séguéla P, Paquet ME, Sharif-Naeini R. Modulating the activity of human nociceptors with a SCN10A promoter-specific viral vector tool. Neurobiol Pain. 2023
Presenting Author
Reza Sharif Naeini
Poster Authors
Reza Sharif Naeini
PhD
McGill University
Lead Author
Magali Millecamps
McGill University
Lead Author
Catherine Theriault
McGill University
Lead Author
Lois S. Miraucourt
McGill University
Lead Author
Hugues Petitjean
McGill University
Lead Author
Miltiadis Georgiopoulos
McGill University Health Center
Lead Author
Jean A. Ouellet
McGill University Health Center
Lead Author
Topics
- Models: Chronic Pain - Inflammatory