Cannabis constituent synergy in a mouse neuropathic pain model

Abstract

Cannabis and its psychoactive constituent Δ9-tetrahydrocannabinol (THC) have efficacy against neuropathic pain, however, this is hampered by their side effects. It has been suggested that co-administration with another major constituent cannabidiol (CBD) might enhance the analgesic actions of THC and minimise its deleterious side effects. We examined the basis for this phytocannabinoid interaction in a mouse chronic constriction injury (CCI) model of neuropathic pain. Acute systemic administration of THC dose-dependently reduced CCI-induced mechanical and cold allodynia, but also produced motor incoordination, catalepsy, and sedation. Cannabidiol produced a lesser dose-dependent reduction in allodynia, but did not produce the cannabinoid side effects. When co-administered in a fixed ratio, THC and CBD produced a biphasic dose-dependent reduction in allodynia. At low doses, the THC:CBD combination displayed a 200-fold increase in anti-allodynic potency, but had lower efficacy compared with that predicted for an additive drug interaction. By contrast, high THC:CBD doses had lower potency, but greater anti-allodynic efficacy compared with that predicted for an additive interaction. Only the high dose THC:CBD anti-allodynia was associated with cannabinoid side effects and these were similar to those of THC alone. Unlike THC, the low dose THC:CBD anti-allodynia was not cannabinoid receptor mediated. These findings demonstrate that CBD synergistically enhances the pain-relieving actions of THC in an animal neuropathic pain model, but has little impact on the THC-induced side effects. This suggests that low dose THC:CBD combination treatment has potential in the treatment of neuropathic pain.

Plant-Based Cannabinoids for the Treatment of Chronic Neuropathic Pain

“…Cannabidiol is the primary non-psychoactive component of Cannabis sativa and has anti-inflammatory, neuroprotective, anxiolytic, and anti-psychotic actions, but does not produce the typical cannabinoid side effects [ 12 , 14 ]. While the actions of THC are at least partly mediated by CB1 and CB2 receptors, the actions of cannabidiol are only partly mediated by CB2 receptors, with other receptor systems having a major role in its activity [ 10 , 15 ].…”

“…THC has been shown to abolish the mechanical and thermal allodynia associated with various neuropathic pain models in rodents [ 15 , 37 , 38 , 39 , 40 ]. However, in addition to analgesia, THC also produces classic cannabinoid side effects such as sedation, catalepsy, reduced locomotion, and hypothermia [ 21 , 24 , 26 , 41 ].…”

“…One important issue with these studies is that they rarely determine the window between the doses at which drugs produce analgesia and side-effects. We have recently shown that THC has a therapeutic index of approximately 5–6, i.e., it produces analgesia with an ED 50 5–6 times lower than that at which it produces side-effects [ 15 ]. Unfortunately, this is a relatively small separation between analgesia and side-effects, albeit better than synthetic cannabinoid agonists (such as WIN55212) which have therapeutic indices of near unity, i.e., no window between analgesia and side-effects [ 42 , 43 , 44 ].…”

Terpenoids Commonly Found in Cannabis sativa Do Not Modulate the Actions of Phytocannabinoids or Endocannabinoids on TRPA1 and TRPV1 Channels

“…These studies have revealed great complexity in the interaction, with CBD synergistically enhancing or inhibiting the effects of D 9 -THC dependent on the measured variable and the frequency of dosing. [7][8][9][10] It has also been hypothesised that the varying effects of different cannabis chemovars might be due to variation in their terpene content, which can reach concentrations of 3.5% and 10% in flower and trichomes, respectively. [11][12][13] However, few studies have addressed this hypothesis; thus, the present study sought to advance the evidence base on potential terpenoid-cannabinoid interactions.…”

Cannabinoid interactions with ion channels and receptors

“…Cannabis sativa, a plant known more commonly as marijuana, has become widely popular due to its induced psychological and euphoric states in an individual who ingests or smokes the plant. More interestingly, the cannabinoids that cause these desired effects also have potential health applications which have been seen to improve a variety of symptoms such as neuropathic pain, seizures, social defects, brain damage from stroke, and lung function in inflammatory lung disease [1][2][3][4][5][6][7][8]. The most popularly used compounds recreationally and therapeutically, Cannabidiol (CBD) and trans-Δ⁹-tetrahydrocannabinol (THC) (Figure 1), are classified as phytocannabinoids since they naturally occur from the Cannabis plant [9].…”