CB2 AGONIST INHIBITS ACTIVATION OF GLIAL CELLS IN CANCER-INDUCED BONE PAIN

Nicole Williams , Alysia Lozano-Ondoua, Todd W Vanderah, Lindsey Anderson, Ashley Symons

CB2 AGONIST INHIBITS ACTIVATION OF GLIAL CELLS IN CANCER-INDUCED BONE PAIN

Currently opiates are used to alleviate serious and chronic pain in cancer patients. Chronic administration of morphine exacerbates cancer-induced pain and accelerates cancer-induced bone destruction in a murine bone cancer model. Additionally, sustained opioids induce many adverse events such as analgesic tolerance, constipation, respiratory depression and somnolence. Thus, there is a need for more effective therapeutics to reduce cancer pain besides opiates. The cannabinoid receptor 2 (CB2) agonist acts as an analgesic to treat inflammatory and neuropathic pain. We hypothesize the CB2 agonist inhibits pain by modulating the expression of glial cells, particularly microglia and astrocytes, in the CNS. Cancer cells or media were surgically implanted into the femur and treated with the selective CB2 agonist, JWH015 (i.t.) or vehicle. Using western blot and ELISA the spinal cords were examined to determine the expression of microglia (Iba1), astrocytes (GFAP), and release of pro-inflammatory mediators. By day 14, cancer inoculated animals treated with CB2 agonist showed a significant reduction of spontaneous pain behaviors, demonstrated by a reduction in the number of flinches and a duration of time spent guarding compared to the cancer inoculated animals treated with vehicle. Also, JWH015 significantly attenuated cancer-induced evoked pain, evidenced by an increase of paw withdrawal threshold, compared to vehicle treated animals. In this cancer model, we found an increase of the expression of GFAP and Iba1 in the lumbar spinal cord, markers of astrocytes and microglia respectively, compared to animals inoculated with cell free media. Furthermore, intrathecal administration of JWH015 in cancer-induced animals released less cytokines (pg/mL), specifically IL6 and TNFα, within the spinal cord implicating CB2 agonists modulate glial activity in the CNS. These findings support our hypothesis that the CB2 agonist reduced pain by inhibiting the activation of glial cells subsequently reducing the amount of cytokines released.

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