Intrathecal Administration of the Cannabinoid 2 Receptor Agonist JWH015 Can Attenuate Cancer Pain and Decrease mRNA Expression of the 2B Subunit of N-Methyl-D-Aspartic Acid

Abstract

Cannabinoids bind to cannabinoid receptors type 1 and 2 and produce analgesia in several pain models, but central side effects from cannabinoid 1 receptors limit their clinical use. Because of the pain-relieving effects of cannabinoid 2 (CB2) receptor agonists in inflammation pain, incision pain, and neuropathic pain models, we tested whether spinal CB2 receptor activation would induce antihyperalgesia in cancer pain. Our previous study showed that the 2B subunit of N-methyl-D-aspartate (NR2B) receptor in the spinal cord participates in bone cancer pain in mice. In the present study, we also tested the cannabinoid effect on the expression of NR2B. Seventy-two mice were randomly allocated to 7 different groups: (1) control; (2) sham and tumor-bearing mice, which include (3) V; (4) J1; (5) J2; (6) J3; and (7) J4. In the groups of tumor-bearing mice, C(3)H/Hej mice were implanted with NCTC2472 fibrosarcoma cells into the femur bone to induce bone cancer-related pain behaviors. The sham mice were implanted with minimal essential medium α modification, whereas the control mice received no injection. On day 14 after implantation, tumor-invoked tactile allodynia and thermal hyperalgesia were assessed. Tumor-bearing mice were assigned to intrathecal administration of the CB2 receptor agonist JWH015 (0.5, 1, and 2 μg), CB2 receptor antagonist AM630 (2 μg), or vehicle, and the assessment of withdrawal thresholds was then performed. Tactile allodynia and thermal hyperalgesia were assessed before administration and at 1 hour, 6 hours, 12 hours, 24 hours, 48 hours, and 72 hours after administration. Spinal NR2B activation of all tumor-bearing mice at 12 hours and 72 hours were determined by reverse transcription-polymerase chain reaction analyses. At day 14 after operation, tumor-evoked tactile allodynia and thermal hyperalgesia were higher in tumor-bearing mice compared with the sham and control mice. Intrathecal administration of JWH015 dose dependently attenuated tumor-evoked tactile allodynia and thermal hyperalgesia but this effect was prevented by intrathecal administration of AM630 30 minutes before. The mRNA expression of NR2B was similar to this result. At 12 hours after administration, the expression of NR2B mRNA in the spinal cord was lower in mice that were administered JWH015 compared with the vehicle group. However, this phenomenon was reversed in the group that was preadministered AM630. These data indicated that intrathecal administration of cannabinoid receptor agonists might relieve cancer pain, probably by reducing NR2B-dependent activity in the spinal cord. These results also suggested that cannabinoids might be a useful alternative or adjunct therapy for relieving cancer pain.