Abstract
Bone cancer pain is the most severe among cancer pain and is often resistant to current analgesics. Thus, the development of novel analgesics effective at treating bone cancer pain are desired. Platelet-activating factor (PAF) receptor antagonists were recently demonstrated to have effective pain relieving effects on neuropathic pain in several animal models. The present study examined the pain relieving effect of PAF receptor antagonists on bone cancer pain using the femur bone cancer (FBC) model in mice. Animals were injected with osteolytic NCTC2472 cells into the tibia, and subsequently the effects of PAF receptor antagonists on pain behaviors were evaluated. Chemical structurally different type of antagonists, TCV-309, BN 50739 and WEB 2086 ameliorated the allodynia and improved pain behaviors such as guarding behavior and limb-use abnormalities in FBC model mice. The pain relieving effects of these antagonists were achieved with low doses and were long lasting. Blockade of spinal PAF receptors by intrathecal injection of TCV-309 and WEB 2086 or knockdown of the expression of spinal PAF receptor protein by intrathecal transfer of PAF receptor siRNA also produced a pain relieving effect. The amount of an inducible PAF synthesis enzyme, lysophosphatidylcholine acyltransferase 2 (LPCAT2) protein significantly increased in the spinal cord after transplantation of NCTC 2472 tumor cells into mouse tibia. The combination of morphine with PAF receptor antagonists develops marked enhancement of the analgesic effect against bone cancer pain without affecting morphine-induced constipation. Repeated administration of TCV-309 suppressed the appearance of pain behaviors and prolonged survival of FBC mice. The present results suggest that PAF receptor antagonists in combination with, or without, opioids may represent a new strategy for the treatment of persistent bone cancer pain and improve the quality of life of patients.
Highlights
Pain in cancer is produced by pressure on, or chemical stimulation of, specialized pain-signalling nerve endings called nociceptors or it may be caused by damage or illness affecting nerve fibers themselves which is responsive to stimuli that are normally non-painful; allodynia
It has been reported that toll-like receptor (TLR) 4, which plays an important role in glial activation in neuropathic pain increased in the spinal expression of a rat model of cancer-induced bone pain and intrathecal injection of TLR4 siRNA or TLR4 signaling pathway blockers led to a pain relieving effect at an early stage, but not at day 16 of cancer-induced bone pain [15]
The present study demonstrated that intravenous administration of platelet-activating factor (PAF) receptor antagonists, TCV-309, BN 50739 and WEB 2086, effectively ameliorated allodynia and pain behaviors such as guarding and limb-use abnormalities in femur bone cancer (FBC) mice
Summary
Pain in cancer is produced by pressure on, or chemical stimulation of, specialized pain-signalling nerve endings called nociceptors (nociceptive pain) or it may be caused by damage or illness affecting nerve fibers themselves (neuropathic pain) which is responsive to stimuli that are normally non-painful; allodynia. A PAF receptor antagonist, CV-3988, injected near the dorsal root ganglion (DRG) in rats or mice lacking PAF receptors showed a reduction in tactile allodynia following spinal nerve injury [6]. Intrathecal injection of the PAF receptor antagonist, WEB 2086, a benzodiazepine derivative for 9 days post-surgery in rats suppressed the development of mechanical allodynia in a rat spared nerve injury model [7]. PAF receptor antagonists, TCV-309 (PAF related), BN 50739 (natural product related compound), and WEB 2086, produced profound and long lasting anti-allodynia effects in several different neuropathic pain models in mice, including a partial sciatic nerve ligation injury model, a partial infraorbital nerve ligation model, a chronic constriction of the infraorbital nerve injury model (CCI model) and a streptozotocin (STZ)-induced diabetes model [8]. The evidence suggests that PAF contributes to neural tissue damage and pain behavior after nerve injury
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