An evaluation of the anti-hyperalgesic effects of cannabidiolic acid-methyl ester in a preclinical model of peripheral neuropathic pain

  • Br J Pharmacol. 2020 Jun;177(12):2712-2725. doi: 10.1111/bph.14997.
Yong Fang Zhu  1  2 ,  Katja Linher-Melville  1  2 ,  Mohammad Javad Niazmand  2 ,  Manu Sharma  2 ,  Ayesha Shahid  2 ,  Kan Lun Zhu  2 ,  Natalka Parzei  2 ,  Jesse Sidhu  2 ,  Christeene Haj  3 ,  Raphael Mechoulam  3 ,  Gurmit Singh  1  2
Affiliations
  • 1. Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada.
  • 2. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
  • 3. Institute for Cannabinoid Research, Hebrew University Medical Faculty, Jerusalem, Israel.
PMID: 31981216 DOI: 10.1111/bph.14997
Abstract

Background and purpose: Chronic neuropathic pain (NEP) is associated with growing therapeutic cannabis use. To promote quality of life without psychotropic effects, cannabinoids Other than Δ9-tetrahydrocannabidiol, including cannabidiol and its precursor cannabidiolic acid (CBDA), are being evaluated. Due to its instability, CBDA has been understudied, particularly as an anti-nociceptive agent. Adding a methyl ester group (CBDA-ME) significantly enhances its stability, facilitating analyses of its analgesic effects in vivo. This study examines early treatment efficacy of CBDA-ME in a rat model of peripherally induced NEP and evaluates sex as a biological variable.

Experimental approach: After 14 consecutive days of intraperitoneal CBDA-ME administration at 0.01, 0.1 and 1 μg·kg-1 , commencing 1 day after surgically implanting a sciatic nerve-constricting cuff to induce NEP, the anti-nociceptive efficacy of this cannabinoid was assessed in male and female Sprague-Dawley rats relative to vehicle-treated counterparts. In females, 2 and 4 μg·kg-1 daily doses of CBDA-ME were also evaluated. Behavioural tests were performed for hind paw mechanical and thermal withdrawal thresholds once a week for 8 weeks. At endpoint, in vivo electrophysiological recordings were obtained to characterize soma threshold changes in primary sensory neurons.

Key results: In males, CBDA-ME elicited a significant concentration-dependent chronic anti-hyperalgesic effect, also influencing both nociceptive and non-nociceptive mechanoreceptors, which were not observed in females at any of the concentrations tested.

Conclusion and implications: Initiating treatment of a peripheral nerve injury with CBDA-ME at an early stage post-surgery provides anti-nociception in males, warranting further investigation into potential sexual dimorphisms underlying this response.

Products