Single and Combined Effects of Cannabinoids on Neuropathic Pain and Cognition

Abstract

Rationale. For centuries, medications derived from the marijuana plant have been used for therapeutic purposes across numerous cultures. In 1964, the primary psychoactive ingredient in cannabis, delta-9-tetrahydrocannabinol (-9-THC) was defined. This, followed by the discovery of the endocannabinoid system, marked the beginning of comprehensive research into the beneficial exploitation of this system. The cannabis plant contains various other cannabinoids besides -9-THC. Most of the effects of cannabinoid-based therapies are based on the agonistic action of -9-THC through cannabinoid receptors. Alternatively, some of these effects are caused by the actions of other cannabinoids, like cannabidiol, which does not have high affinity for cannabinoid receptors. Like -9-THC, cannabidiol (CBD), the non-psychoactive phytocannabinoid in Cannabis sativa, has been hypothesized to ameliorate adverse effects of -9-THC. Cannabidiol possesses neuroprotective, antiemetic, and anti-inflammatory properties. Sativex, a 1:1 ratio of CBD and -9-THC, is currently an approved medication in Europe for the treatment of conditions such as neuropathic pain, and has been fast tracked by the USFDA for late stage clinical trials for a host of disorders, ranging from epilepsy to irritable bowel disease. Additionally, increasing preclinical evidence demonstrates that treatment with Cannabidiol alone produces efficacy on a variety of nervous system injuries, including neuropathic pain, schizophrenia and anxiety disorders. Furthermore, there is mounting evidence of an “entourage effect” in cannabinoid-based pharmacotherapies. This effect occurs when treatment with a combination of cannabinoids derived from the plant produce more efficacy than treatment with a single cannabinoid (1). As cannabinoid-based treatments continue to develop and clinical data increases, further investigation of the entourage effect is necessary to facilitate the appropriate future treatment regimens for nervous system disorders. Hypotheses. We hypothesized that treatment with the non-psychoactive cannabis compound cannabidiol would be as effective as the psychoactive cannabis compound -9-THC, or a combination of the two, in mitigating neuropathic pain in a mouse model of chemotherapy-induced peripheral neuropathy. We additionally hypothesized that cannabidiol would not affect classic cannabinoid-agonist induced cognitive impairment in rodent models of learning and memory. Methodology. Neuropathic pain was induced by repeated injections of the chemotherapeutic agent Paclitaxel. Mechanical hypersensitivity to Paclitaxel was assessed using the Von Frey assay. Cognition was assessed using three rodent models of learning and memory: 1) Conditional Discrimination, 2) Conditional Discrimination with a reversal component, and 3) Barnes Maze. Results. Cannabidiol was found to be more potent and more effective than -9-THC in attenuating neuropathic pain in a dose dependent manner. Combinations of CBD+-9-THC revealed that lower, ineffective doses of CBD and -9-THC display supra-additive effects when given in combination while higher, individually effective doses exhibit sub-additive effects in combination. Cognitively, no deficits were observed over a range of doses of any cannabinoid tested in the conditional discrimination tasks, although a slight trend was observed in animals administered the synthetic mixed CB1/CB2 agonist WIN55,212-2. In the Barnes Maze task, treatment with -9-THC alone dose-dependently decreased number of entries and total time spent in the target zone. Cannabidiol did not produce any effects in the Barnes Maze alone, nor did it attenuate the effects seen in animals treated with -9-THC alone. Lastly, -9-THC did not affect total distance traveled or average speed, whereas combination treatment increased both locomotor measurements at all but the highest combination dose. Conclusions. The results of these studies indicate that cannabidiol is more potent than -9-THC in attenuating neuropathic pain. Results of cognitive testing indicate subtle impairment in animals treated with -9-THC and WIN55,212-2 that were not reversed by CBD.