ABSTRACT
Causes of cancer pain are multifactorial and complex.It is an important challenge for the clinicians on how to control cancer pain effectively.Opioids remain the most effective analgesics used in the treatment of cancer pain.But the adverse effects and potential risks associated with chronic use have been paid attention to in clinical work.It is related to molecular discoveries of opioid action that lead to the development of new opioid analgesic on potential new targets in treating cancer pain.Meanwhile, non-pharmacological treatments such as neuromodulation and minimally invasive interventional techniques play an important role in management of cancer pain.It is summarized in this article about the recent advances in biology and management of cancer pain.
ABSTRACT
Cionbufagin has anti-inflammatory and analgesic effects. It is of great value in the treatment of bone cancer pain, but its mechanism is still unclear. To generate a bone metastasis model of breast cancer, 4×105 Walker-256 cells were inoculated into the left hind limb of SD rats. The experimental protocol was approved by the Medical Laboratory Animal Ethics Committee of Medical College of China Three Gorges University. Rats were randomly divided into sham, model, cionbufagin, morphine, saline, minocycline, microglia inhibitor (RS102895) and co-treatment with cionbufagin and minocycline group. The cionbufagin (5 mL·kg-1, i.p.), morphine (8 mg·kg-1, i.p.) and co-treatment groups (included cionbufagin 5 mL·kg-1, i.p.) received continuous administration from day 9 to day 21. The saline, minocycline (2.5 μg·μL-1, 20 μL), RS102895 (1.5 μg·μL-1, 20 μL) and co-treatment groups (included minocycline 2.5 μg·μL-1, 20 μL) received continuous administration by intrathecal cannulation from day 12 to day 21. Bone destruction of the left hind limb of rats was detected by hematoxylin-eosin staining (H&E). The pain threshold before treatment and at day 2, 5, 7, 9, 12, 14, 17 and 20 was measured by behavioral indexes. Activation and expression of a microglia marker (Iba-1) was determined by immunofluorescence and Western blot. The level of tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6) in rat spinal cord was measured by enzyme-linked immunosorbent assay (ELISA). H&E results showed that cionbufagin effectively inhibited the destruction of bone marrow in rats with bone cancer pain; cionbufagin treatment significantly increased the mechanical and thermal pain threshold. Immunofluorescence showed that cionbufagin effectively inhibited the activation of microglia in the spinal dorsal horn. Western blot analysis confirmed that the activation of microglia in the spinal dorsal horn was inhibited by cionbufagin treatment. It was also found that the CCL2/CCR2 pathway may be involved in the analgesic effect of cionbufagin. These results suggest that cionbufagin can effectively alleviate bone cancer pain, possibly by inhibiting the release of inflammatory factors and the activation of spinal microglia cells through the CCL2/CCR2 pathway.
ABSTRACT
OBJECTIVE@#To observe the effect of cinobufagin on transient outward potassium current () in rat dorsal root ganglion cells of cancer-induced bone pain (CIBP) and explore the possible analgesic mechanism of cinobufagin.@*METHODS@#Whole cell patch clamp technique was used to examine the effect of cionbufagin on in acutely isolated dorsal root ganglion (DRG) cells from normal SD rats and rats with bone cancer pain.@*RESULTS@#The DRG cells from rats with CIBP showed obviously decreased current density, an activation curve shift to the right, and an inactivation curve shift to the left. Cinobufagin treatment significantly increased the current density and reversed the changes in the activation and inactivation curves in the DRG cells.@*CONCLUSIONS@# current is decreased in DRG neurons from rats with CIBP. Cinobufagin can regulate the activation and inactivation of current in the DRG cells, which may be related to its analgesic mechanism.
Subject(s)
Animals , Rats , Analgesics , Pharmacology , Bufanolides , Pharmacology , Cancer Pain , Drug Therapy , Cells, Cultured , Ganglia, Spinal , Patch-Clamp Techniques , Potassium Channels , Metabolism , Rats, Sprague-DawleyABSTRACT
Objective: To investigate the efficacy of patients with cancer-induced bone pain (CIBP) treated with morphine in combination with dexamethasone through intrathecal pumping injection and its mechanism. Methods: Seventy-six patients with CIBP undergoing implantation of an infusion port with intrathecal catheter were randomly divided into group A (n = 38, intrathecally injected with morphine alone and group B (n = 38, intrathecally injected with morphine in combination with dexamethasone). The pain relief degree by 11-Point Numeric Rating Scale (NRS-11) score, the frequency of breakthrough pain, quality of life and SF-36 scale score were evaluated before treatment and the 1st, 3rd and 7th days after the beginning of intrathecal pumping. On the 7th day after treatment, the concentrations of â-endorphin (â-EP) and motilin in plasma as well as prostaglandin E2 (PGE2), substance P (SP) and calcitonin gene-related peptide (CGRP) in cerebrospinal fluid (CSF) were determined. Results: The pain was relieved significanly in group B, and the frequencies of breakthrough pain per day were less than those in group A on the 1st, 3rd and 7th days after treatment (all P 0.05); in group B, the SF-36 scale score and quality of life were both improved significantly on the 3rd and 7th days after treatment as compared with those of group A (all P 0.05), but the motilin level in plasma in group B was significantly higher than that in group A (P < 0.05); the PGE2, SP and CGRP levels in CSF in group B were significantly lower than those in group A (all P < 0.05). Conclusion: Intrathecal pumping injection of morphine in combination with dexamethasone can be of great help in decreasing the frequency of breakthrough of CIBP, improving the quality of life, and increasing the motilin level in plasma, but decreasing PGE2, SP and CGRP levels in CSF which may contribute to alleviating the tolerance of morphine, thus enhance the analgesic effect.
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Objective To explore the efficacy of electroacupuncture treatment in cancer induced bone pain (CIBP)-morphine tolerance rat model and the expression of calcitonin-gene related peptide(CGRP) immunohistochemisty in dorsal root ganglion (DRG).Methods Forty SD rats were divided into four groups:sham group,CIBP + morphine tolerance group (BM),CIBP + electroacupuncture group (BE),and CIBP + morphine tolerance + electroacupuncture group (BME).BM,BE and BME groups were prepared CIBP model by carcinoma cell tibia implanted.After six days,the three CIBP groups accepted treatment of morphine,electroacupuncture,and morphine combined electroacupuncture,separately,nine days continuously.Acupoints were selected Zusanli (ST36) and Sanyinjiao (SP6).50％ mechanical withdraw threshold was evaluated by mechanical stimulation.CGRP expression in dorsal root ganglion was detected by immunohistochemisty.Results After five days of electroacupuncture treatment,pain threshold was (10.9 ± 0.8) g in BME group,(8.7 ± 0.6) g in BM group and (6.2 ± 0.9) g in BE group.The results had significant statistic differences (P ＜ 0.01,separately).IOD value of CGRP expression in dorsal root ganglion was 9026.5 ± 1827.4 in BME group,compared with 14803.1 ± 2086.7 in BM group and 15730.6 ± 2712.5 in BE group (P ＜ 0.01,separately).Results Electroacupuncture can relieve CIBP-morphine tolerance rat pain behavior.The mechanism is related to inhibiting CGRP overdue expression in DRG.
ABSTRACT
Descending nociceptive modulation from the supraspinal structures plays an important role in cancer-induced bone pain (CIBP).Rostral ventromedial medulla (RVM) is a critical component of descending nociceptive facilitation circuitry,but so far the mechanisms are poorly known.In this study,we investigated the role of RVM glial activation in the descending nociceptive facilitation circuitry in a CIBP rat model.CIBP rats showed significant activation of microglia and astrocytes,and also up-regulation of phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) and pro-inflammatory mediators released by glial cells (IL-1β,IL-6,TNF-a and brain-derived neurotrophic factor) in the RVM.Stereotaxic microinjection of the glial inhibitors (minocycline and fluorocitrate) into CIBP rats' RVM could reverse the glial activation and significantly attenuate mechanical allodynia in a time-dependent manner.RVM microinjection of p38 MAPK inhibitor (SB203580) abolished the activation of microglia,reversed the associated up-regulation of pro-inflammatory mediators and significantly attenuated mechanical allodynia.Taken together,these results suggest that RVM glial activation is involved in the pathogenesis of CIBP.RVM microglial p38 MAPK signaling pathway is activated and leads to the release of downstream pro-inflammatory mediators,which contribute to the descending facilitation of CIBP.