KannaLife Sciences Inc. — Department of Health and Human Services STTR Phase I: NIDA

Description

Chemotherapy induced peripheral neuropathyCIPNcan be a chronicseverely debilitating consequence of cancer therapy for which there are no effective management strategiesMoreoverupwards ofof CIPN patients reported using prescription opioids for pain management despite the fact that there is only weak evidence that long term continuation of opioids provides clinically significant pain relief in these patientsMitochondrial dysfunctionoxidative stressand inflammation have all been implicated in its etiologyWe have shown that the non psychoactive cannabinoid cannabidiolCBDprevents the development of CIPN in a mouse model of paclitaxel induced cold and mechanical allodyniaIn vitrowe observe that paclitaxel increases microglial expression of several putative mediators of neuropathic painand that this effect can be blocked by CBD in a mitochondrial NaCaexchangermNCXdependent mannerWe have also recently shown that a more potenthydrophilic analogue of CBDKLSprotects against paclitaxel induced oxidative stress in cultured dorsal root ganglia neuronsand that the mechanism underlying this neuroprotection is also regulation of intracellular calcium via the mNCXPreliminary results demonstrate that KLScan attenuate mechanical sensitivity associated with CIPN while also reducing microglial activation and T cell infiltration into the spinal cordOur central hypothesis is that administration of CBD or KLShelps preserve Cahomeostasis by promoting activity of the mNCXwhich in turn protects from both mitochondrial dysfunction and microglial activation to prevent the neuronal and glial changes associated with the development and maintenance of paclitaxel induced neuropathic painResults from experiments in AIMwill demonstrate that the neuroprotective properties of CBD and KLScan be reduced by pharmacological or gene knockdown of the mNCX in a statistically significant mannerResults from experiments in AIMwill further confirm the i pand p oefficacy of KLSvs CBD to prevent or reverse mechanical sensitivity and neuroinflammation in a mouse model of paclitaxel induced neuropathic pain and that repeated administration of these compounds does not lead to analgesic toleranceRemarkablythe nonpsychoactive CBD has also been shown to inhibit cue induced heroin seeking and neurochemical correlates thereof in a rat model of relapse and decrease heroin craving in a small human studyExperiments in AIMare designed to test the hypothesis that KLSand CBD will attenuate reinstatement of morphine seeking behavior in a rat model of opioid relapseThe overall impact of the results from the proposed research will be significant advancements intoidentification of specific mechanisms that induce CIPNapplication of this knowledge to facilitate design of novel treatment strategies for neuropathic painandnovel treatment strategies to reduce or replace prescription opioid use and decrease prescription opioid abuse Chemotherapy induced peripheral neuropathyCIPNcan be a chronicseverely debilitating consequence of cancer therapy for which there are no effective management strategiesMoreoverupwards ofof CIPN patients reported using prescription opioids for pain managementdespite the weak evidence of their efficacy and the risks of long term dependenceMitochondrial dysfunctioncalcium dysregulationoxidative stressand inflammation have all been implicated in its etiologyCannabidiolCBDis a non psychoactive component of Cannabis sativa is effective in both treating CIPN and relieving opiate dependenceHoweverCBD has severe limitations in terms of potencysafetyoral bioavailabilityand regulatory restrictionsKannalife has solved these problems in its patented series of derivatives that include KLSThis grant will demonstrate the efficacy of KLSin models of CIPN and opiate dependenceand will further elucidate its mechanism of action in regulation of calcium levels and inflammatory sequelae