am-1241 and Cancer-Pain

Cancer pain seriously affects the life quality of patients. Morphine is commonly used for cancer pain, but tolerance development limits its clinical administration. Central immune signaling is important in the development of cancer pain and morphine tolerance. Cannabinoid receptor 2 (CB2) inhibits cancer pain and morphine tolerance by regulating central immune signaling. In the present study, we investigated the mechanisms of central immune signaling involved in morphine tolerance inhibition by the CB2 agonist AM1241 in cancer pain treatment.. Rats were implanted with tumor cells and divided into 4 groups: Vehicle (PBS), 0.07 μg AM1241, 0.03 μg AM1241, and AM630 (10 μg) + AM1241 (0.07 μg). All groups received morphine (20 μg/day, i.t.) for 8 days. AM630 (CB2 antagonist) was intrathecally injected 30 min before AM1241, and AM1241 was intrathecally injected 30 min before morphine. The spinal cord (SC) and dorsal root ganglion (DRG) were collected to determine the expression of Toll-like receptor 4 (TLR4), the p38 mitogen-activated protein kinase (MAPK), microglial markers, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α.. The expression of TLR4, p38 MAPK, microglial markers, IL-1β, and TNF-α was significantly higher in AM1241-pretreated groups than in the vehicle group (P < 0.05). No difference in microglial markers, IL-1β, and TNF-α expression was detected in the AM630 + AM1241 group compared with the vehicle group.. Our results suggest that in a cancer pain-morphine tolerance model, an i.t. non-analgesic dose of AM1241 induces microglial activation and IL-1β TNF-α upregulation in SC and DRG via the CB2 receptor pathway.

Topics: Animals; Cancer Pain; Cannabinoids; Catheterization; Drug Tolerance; Ganglia, Spinal; Hyperalgesia; Immune System; Interleukin-1beta; Male; Morphine; p38 Mitogen-Activated Protein Kinases; Pain Threshold; Rats; Rats, Wistar; Receptor, Cannabinoid, CB2; Signal Transduction; Spinal Cord; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Morphine is widely used as an analgesic to treat moderate to severe pain, but chronic morphine use is associated with development of tolerance and dependence, which limits its analgesic efficacy. Our previous research has showed that nonanalgetic dose of a cannabinoid type 2 (CB2) receptor agonist reduced morphine tolerance in cancer pain. A previous study showed the colocalization of CB2 and transient receptor potential vanilloid 1 (TRPV1) in human and rat dorsal root ganglia (DRG) sensory neurons. Whether coadministration of a CB2 receptor agonist and morphine could reduce TRPV1 expression in morphine‑induced antinociception and tolerance in cancer pain is unclear. Therefore, we investigated the effects of coadministration of a CB2 receptor agonist AM1241 and morphine on TRPV1 expression and tolerance in cancer pain. Coadministration of AM1241 and morphine for 8 days significantly reduced morphine tolerance, as assessed by measuring paw withdrawal latency to a radiant heat stimulation, in Walker 256 tumor‑bearing rats. Repeated morphine treatment for a period of 8 days induced upregulation of the TRPV1 protein expression levels in the DRG in the tumor‑bearing rats, although no change in mRNA expression. Pretreatment with AM1241 reduced this morphine‑induced upregulation of TRPV1 and the effect was reversed by the CB2 receptor antagonist AM630. Our findings suggest that coadministration of a CB2 receptor agonist AM1241 and morphine reduced morphine tolerance possibly through regulation of TRPV1 protein expression in the DRG in cancer pain.

Topics: Analgesics, Opioid; Animals; Cancer Pain; Cannabinoid Receptor Agonists; Cannabinoids; Disease Models, Animal; Down-Regulation; Drug Tolerance; Ganglia, Spinal; Indoles; Male; Morphine; Rats; Rats, Wistar; TRPV Cation Channels