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

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 μgÁkg −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 μgÁkg −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 nonnociceptive 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.

(‒)-Cannabidiolic Acid, a Still Overlooked Bioactive Compound: An Introductory Review and Preliminary Research

“…This finding was in line to the synthesis of cannabidiolic acid methyl ester (HU-580), whose chemical features, slightly different from its natural precursor, seem to encompass CBDA chemical instability, and its susceptibility to decarboxylation [37]. Recent findings state that HU-580 also positively affects the sleep-wake cycle in male Wistar rats [38], and still CBDA anti-nociceptive activity was enhanced following methyl ester group addition [39]. The potential CBDA anti-inflammatory activity continues to be the main focus for deepened investigations.…”

Evaluation of the preclinical analgesic efficacy of naturally derived, orally administered oil forms of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and their 1:1 combination

“…In females, none of the cannabis-derived oil formulations tested in the current investigation prevented the onset or further progression of mechanical hypersensitivity in response to sustained peripheral nerve constriction. Using the nerve cuff model, our group has observed a similar sexual dimorphism in behavioural treatment responsiveness to intraperitoneally injected cannabidiolic acid (CBDA)-methyl ester, a stabilized form of naturally derived CBDA that is a precursor of CBD [46].…”

“…The acute intracellular electrophysiological recording techniques have been reported previously in animal models of NP [40,41,43,46] and cancer pain [47,48]. After the last behavioural test was performed during week 9 (day 63 post-nerve cuff surgery), each rat was initially anesthetised with an intraperitoneally delivered mixture of acepromazine, ketamine, and xylazine.…”

“…In addition, it will be important to examine whether administering a higher oral dose of each cannabinoid, in oil form, to females could reverse mechanical hypersensitivity. However, we have shown that administering significantly higher concentrations of CBDA-methyl ester (CBDA-ME), a synthetic derivative of the naturally occurring precursor of CBD, to female rats implanted with a sciatic nerve cuff failed to reverse this response, with males undergoing complete recovery even at very low doses [46]. A plethora of research is now emerging in support of fundamental sex differences in nociceptive signaling, at least in response to a variety of treatment regimens including metformin [97] and, as recently reported by our group, pregabalin and progesterone [57].…”

Sex differences in neuro(auto)immunity and chronic sciatic nerve pain

“…Preclinical studies based on sciatic nerve injury in rodents are frequently used to cost-effectively provide a model of neuropathic pain [37] and are therefore being used to examine sexually dimorphic outcomes. Indeed, behavioral and electrophysiological research by our group has shown that this type of pain persists in female rodents, while males respond well to various agents that have been tested to date [38][39][40].…”