Orally consumed cannabinoids provide long-lasting relief of allodynia in a mouse model of chronic neuropathic pain

Chronic pain affects a significant percentage of the United States population, and available pain medications like opioids have drawbacks that make long-term use untenable. Cannabinoids show promise in the management of pain, but long-term treatment of pain with cannabinoids has been challenging to implement in preclinical models. We developed a voluntary, gelatin oral self-administration paradigm that allowed animals to consume Δ9-tetrahydrocannabinol, cannabidiol, or morphine ad libitum. Animals stably consumed these gelatins over 3 weeks, with detectable serum levels. We designed a real-time gelatin measurement system, and observed that mice consumed gelatin throughout the light and dark cycles, with THC-gelatin animals consuming less than the other groups. Consumption of all three gelatins reduced measures of allodynia in a chronic, neuropathic sciatic nerve injury model, but tolerance to morphine developed after one week while THC or CBD reduced allodynia over three weeks. Hyperalgesia took longer to develop after sciatic nerve injury, but by the last day of testing THC significantly reduced hyperalgesia responses, with a trend effect of CBD, and no effect of morphine. Mouse vocalizations were recorded throughout the experiment, and mice showed a large increase in ultrasonic, broadband clicks after sciatic nerve injury, which was reversed by both THC and CBD. This study demonstrates that mice will voluntarily consume both cannabinoids and opioids via gelatin, and that cannabinoids can provide long-term relief of chronic pain states. Additionally, ultrasonic clicks may objectively represent the pain status of a mouse and could be integrated into future pain models.