| Bone cancer pain, caused usually by primary bone cancer or secondary bone metastasis of the cancers originating from visceral organs, is one of the most serious cancer pains and severely impairs the quality of the patients’life. However, it is said that almost half of the patients with cancer cannot underwent the adequate management of the cancer pain. So it is important to understand the underlying mechanisms of the cancer pain and search the potential therapeutic targets for it. It is generally believed that when chronic pain develop, a variety of neuronal changes developed, including altered excitability of sensory neurons, alterations in which neurotransmitters are synthesized and released by various sensory neurons, alterations in pain transmission neuron excitability via multiple changes in receptor and ion channel functions, and so on.In recent years, it is believed that the realization on alterations in neuronal functions fails to capture all of the critical mechanisms of the cancer pain. So the neuron-glia crosstalk has been more attention. And the idea that glia contribute to pain has gained widespread support. Spinal microglia and astrocytes are activated in almost every animal model with pain, including inflammatory pain, neuropathic pain or bone cancer pain. Drugs that inhibit glial activation or their proinflammatory products can reverse the pain states.Although it is clear that chronic pain activates spinal cord glia, the signals that initiate this activation are still unknown. Several mechanisms have been proposed, including fractalkine acting via microglial CX3CR1and ATP acting via the microglial P2X4receptor or P2X7receptor.Recently reports reveal that glia may be activated via stimulation of a member of the toll-like receptor (TLR) family, TLR4. TLR4is expressed on microglia, astrocyte and endothelial cells of the cerebral vessels, in the central nervous system. This receptor is a transmembrane receptor protein with extracellular leucine-rich repeated domains and a cytoplasmic signaling domain and it is involved in immune responses, especially in the activation of innate immunity but also triggers of the acquired immunity. The endotoxin lipopolysaccharide (LPS), a major component of the outer membrane of gram-negative bacteria, is a well known exogenous ligand for TLR4, whereas among its potential endogenous ligands there are heat shock proteins60and70, fibrinogen, fibronectin and oligosaccharides of hyaluronic acid. In the spinal microglia TLR4mRNA expression is increased after L5nerve transection in rats, a model of neuropathic pain. Administration of the TLR4inhibitors LPS-RS can suppress spinal microglial activation and decrease neuropathic pain.It has been proposed that sensory neuron damage leads to the release of heat shock proteins and cell membrane components, which stimulate microglial TLR4in spinal cord, initiating microglial activation. It can detect host DNA, RNA, heat shock proteins, cell membrane components. In neuropathic pain, it has been proposed that sensory neuron damage leads to the release of such substances and that these stimulate microglial TLR4in spinal cord, initiating microglial activation. Administering TLR4inhibitors can suppress spinal microglial activation and decrease neuropathic pain.Based on the well established involvement of the TLR4in neuropathic pain, we supposed that TLR4in the spinal cord was an important factor for cancer pain. In this study, we use TLR4inhibitors to investigate the possible role of TLR4in bone cancer pain.Acupuncture is a common treatment for many disease and symptoms, including pain, in traditional Chinese medicine. There is good evidence for the use of acupuncture for painful and non-painful conditions in clinic, such as low back pain, acute dental pain, recurrent headache and nausea and vomiting associated with chemotherapy, pregnancy or post-surgery. Recent studies demonstrate that electroacupuncture (EA), in which electrodes are attached to the acupuncture needles to provide pulsating electrical stimulation, has significant therapeutic effects on rat models of chronic inflammatory, neuropathic, and ankle sprain pain. And our prior study with an animal model of inflammatory pain also showed that10Hz EA at acupoint Huantiao (GB30) significantly attenuates hyperalgesia.Though Electroacupuncture analgesia has been recognized and widely used in clinical, the efficacy in cancer pain is still being questioned。Some research reported that electroacupuncture can attenuates bone cancer-induced hyperalgesia in a rat model, as well as on a mouse model of cutaneous cancer pain, there were fewer clinical report available for its role in palliation of chronic cancer-related pain and the effects of EA on bone cancer pain still have not previously been scientifically investigated. The aim of the present study is to evaluate the efficacy of EA on bone cancer pain in an established rat model。The results are as follows:1. Behavioral testsRats inoculated with mammary gland cancer cells displayed a profound decrease in paw withdrawal threshold to von Frey hair stimulation, not only on the right hind limb received live cells but also on the non-inoculated left limb. A significant decrease in paw withdrawal threshold to von Frey hair stimulation occurs from day8(P<0.05) compared with the normal control rats.2. The change of TLR4mRNA in bone cancer pain of the rat model TLR4mRNA levels of L3-L5lumbar spinal cord segments were significantly increased after unilateral inoculation of cancer cells in comparison to the normal, PBS and Heat-Killed cancer cell injected control rats. Notably, the levels of TLR4were increased moderately at day8and markedly at day16and day22after unilateral inoculation of cancer cells, compared with normal rats by RT-PCR analysis.3. Reversal of bone cancer pain by intrathecally delivery of naloxone,PWT of bone cancer pain model rat was ameliorated by intrathecal administration of Naloxone at day8. As compared to the i.t. NS injection,45min later administration of Naloxone PWT significantly increased in both ispilateral and contralateral. And the effect can last more than3hours. AT day16, intrathecal administration of Naloxone only can increase PWT at the point of45min in contralateral, and there is no significantly change of PWT in ipsilateral compared to NS injection.4. The changes of the IL-1β and TNF-α after naloxone deliver90min after intrathecal injection of the Naloxone at day12, the levels of IL-1β and TNF-α mRNA in L3-L5lumbar spinal dorsal horn were analyzed using semi-quantitative RT-PCR. The results showed that compare to NS injection, after Naloxone intrathecal injection, the IL-1β and TNF-α mRNA were decreased in both sides of spinal dorsal horns.5. Effects of electroacupuncture (EA) on cancer pain relievingIn order to investigate the analgesic effects of EA on cancer pain, EA treatment was applied to the rat model every day, the acupoints, Zu-San-Li and Kun-Lun or Zu-San-Li and Huan-Tiao, were selected in our study. The results showed that EA treatment displayed no significant analgesia effect on bone cancer pain model.Conclusion:The present study suggested that increase expression of TLR4mRNA in bilateral side of spinal dorsal horn was observed in rat tibia bone cancer pain, indicating the TLR-microglia-proinflammatory cytokines pathway might play important role in bone cancer pain and the EA treatment displayed no significant analgesic effect on rat bone cancer pain, suggested EA analgesia correlated with the type of cancer pain. |
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