2022: Mechanistic evaluation of combined Cannabis components cannabidiol and β-caryophyllene in reducing chronic pain in a rat SCI model

Amanda Pacheco-Spiewak
University of Miami

Co-authors: Anjalika Eeswara¹, Shirah Aguayo¹, Stanislava Jergova¹, Jacqueline Sagen^1
1University of Miami

Objective: Medical marijuana is often used to relieve pain, but there is a paucity of preclinical studies which evaluate the effects of cannabis components in a spinal cord injury (SCI) model. Previous studies in our lab have established optimal therapeutic doses of two cannabis components, Cannabidiol (CBD) and β-caryophyllene (BCP), that synergistically or additively attenuate allodynia associated with SCI. To elaborate on our previous findings, 3 aims were pursued in this study: (1) assess for adverse side effects following CBD:BCP coadministration, (2) explore possible mechanisms of action underlying pain reduction, and (3) determine whether long-term CBD:BCP administration reduces opioid-seeking behavior.

Methods: Using male and female Sprague-Dawley rats, spinal cord injuries were induced using a clip compression model at mid-thoracic levels. To assess for adverse side effects, we evaluated disturbances in motor coordination, catalepsy, and body temperature using our highest therapeutic dose. Next, we pretreated with selective CB1, CB2 and opioid antagonists followed by coadministration of CBD:BCP at the pre-determined A50 dose and evaluated for tactile and cold allodynia. Lastly, we used the Conditioned Place Preference (CPP) test with low dose morphine as an analgesic reinforcing agent. CBD:BCP treated or controls were paired with morphine on their non-preferred side and saline on their preferred side, then assessed for CPP.

Results: Coadministration of CBD:BCP did not produce any adverse effects in the behaviors observed. Neither administration of AM630 nor naloxone had any effect on tactile and cold allodynia. However, administration of AM251 reduced or completely blocked the beneficial analgesic effects of CBD:BCP. Furthermore, animals who received CBD:BCP coadministration showed reduced morphine-seeking behavior compared to SCI animals who received morphine only.

Conclusion: These results suggest that CBD:BCP coadministration is both a safe and effective treatment option for SCI-related pain. Further, their use as a supplemental therapeutic agent could potentially reduce opioids needed for effective pain management. Since neither CBD nor BCP are thought to act via the CB1 receptor, our results showing reversal of CBD:BCP analgesic effects by a selective CB1 antagonist suggest potential novel interaction between the 2 components in SCI that may underlie the robust beneficial effects of this combination.