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

Chronic neuropathic pain (NP) is a growing clinical problem for which effective treatments, aside from non-steroidal anti-inflammatory drugs and opioids, are lacking. Cannabinoids are emerging as potentially promising agents to manage neuroimmune effects associated with nociception. In particular, Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and their combination are being considered as therapeutic alternatives for treatment of NP. This study aimed to examine whether sex affects long-term outcomes on persistent mechanical hypersensitivity 7 weeks after ceasing cannabinoid administration. Clinically relevant low doses of THC, CBD, and a 1:1 combination of THC:CBD extracts, in medium chain triglyceride (MCT) oil, were orally gavaged for 14 consecutive days to age-matched groups of male and female sexually mature Sprague Dawley rats. Treatments commenced one day after surgically inducing a pro-nociceptive state using a peripheral sciatic nerve cuff. The analgesic efficacy of each phytocannabinoid was assessed relative to MCT oil using hind paw mechanical behavioural testing once a week for 9 weeks. In vivo intracellular electrophysiology was recorded at endpoint to characterize soma threshold changes in primary afferent sensory neurons within dorsal root ganglia (DRG) innervated by the affected sciatic nerve. The thymus, spleen, and DRG were collected post-sacrifice and analyzed for long-term effects on markers associated with T lymphocytes at the RNA level using qPCR. Administration of cannabinoids, particularly the 1:1 combination of THC, elicited a sustained mechanical anti-hypersensitive effect in males with persistent peripheral NP, which corresponded to beneficial changes in myelinated Aß mechanoreceptive fibers. Specific immune cell markers associated with T cell differentiation and pro-inflammatory cytokines, previously implicated in repair processes, were differentially up-regulated by cannabinoids in males treated with cannabinoids, but not in females, warranting further investigation into sexual dimorphisms that may underlie treatment outcomes.

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

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.

Response to pregabalin and progesterone differs in male and female rat models of neuropathic and cancer pain.

Background: Cancer pain involves nervous system damage and pathological neurogenesis. Neuropathic pain arises from damage to the nervous system and is driven by ectopic signaling. Both progesterone and pregabalin are neuroprotective in animal models, and there is evidence that both drugs bind to and inhibit voltage-gated calcium channels. Aims: This study was designed to characterize the effects of progesterone and pregabalin in preclinical models of cancer and neuropathic pain in both sexes. Methods: We measured peripheral sensory signaling by intracellular in vivo electrophysiology and behavioral indicators of pain in rat models of cancer-induced bone pain and neuropathic pain. Results: Female but not male models of cancer pain showed a behavioral response to treatment and pregabalin reduced excitability in C and A high-threshold but not low-threshold sensory neurons of both sexes. Male models of neuropathic pain treated with pregabalin demonstrated higher signaling thresholds only in A high-threshold neurons, and behavioral data indicated a clear recovery to baseline mechanical withdrawal thresholds in all treatment groups. Female rat treatment groups did not show excitability changes in sensory neurons, but all demonstrated higher mechanical withdrawal thresholds than vehicle-treated females, although not to baseline levels. Athymic female rat models of neuropathic pain showed no behavioral or electrophysiological responses to treatment. Conclusions: Both pregabalin and progesterone showed evidence of efficacy in male models of neuropathic pain. These results add to the evidence demonstrating differential effects of treatments for pain in male and female animals and widely differing responses in models of cancer and neuropathic pain.

Contexte: La douleur cancéreuse implique des lésions du système nerveux et une neurogenèse pathologique. La douleur neuropathique résulte d'une lésion du système nerveux et est provoquée par une signalisation ectopique. La progestérone et la prégabaline sont toutes deux neuroprotectrices dans les modèles animaux et il est prouvé que ces deux médicaments se lient aux canaux calciques à tension contrôlée et les inhibent.Objectifs: Cette étude visait à caractériser les effets de la progestérone et de la prégabaline dans des modèles précliniques de cancer et de douleur neuropathique chez les deux sexes.Méthodes: Nous avons mesuré la signalisation sensorielle périphérique par électrophysiologie intracellulaire in vivo, ainsi que les indicateurs comportementaux de la douleur dans des modèles de rats atteints de douleurs osseuses et de douleurs neuropathiques induites par le cancer.Résultats: Contrairement aux modèles masculins, les modèles féminins atteints de douleur cancéreuse ont montré une réponse comportementale au traitement, tandis que la prégabaline a réduit l'excitabilité des neurones sensoriels C et A à seuil élevé mais non à seuil bas chez les deux sexes. Les modèles masculins atteints de douleur neuropathique traités à la prégabaline ont montré des seuils de signalisation plus élevés uniquement dans les neurones A à seuil élevé, tandis que les données comportementales ont indiqué un net retour aux seuils de retrait mécanique de départ dans tous les groupes de traitement. Les groupes de rats femelles traités n'ont pas montré de changements d'excitabilité dans les neurones sensoriels, mais tous ont montré des seuils de retrait mécanique plus élevés que les femelles traitées avec le vecteur, sans toutefois atteindre les niveaux de départ. Les modèles atteints de douleur neuropathique parmi les rats femelles athymiques n'ont montré aucune réponse comportementale ou électrophysiologique au traitement.Conclusions: La prégabaline et la progestérone ont toutes deux démontré leur efficacité dans les modèles masculins atteints de douleur neuropathique. Ces résultats s'ajoutent aux données probantes démontrant les effets différentiels des traitements de la douleur chez les animaux mâles et femelles, et les réponses très différentes dans les modèles atteints de cancer et de douleur neuropathique.