- model of bone cancer pain. - We investigated the effects of dezocine, a mu- and kappa-opioid receptor agonist/antagonist, on morphine tolerance and explored the involvement of opioid receptor expression in a rat model of bone cancer pain.. - Real-time PCR and western blot analysis were used to examine opioid receptor expression in the periaqueductal gray (PAG) and spinal cord.. - Low-dose dezocine coadministration significantly reversed the downregulated expression of mu (MOR) and delta (DOR) opioid receptors in the PAG and the upregulated expression of kappa (KOR) and DOR in the spinal cord induced by morphine. - Conclusions: The combination of low-dose dezocine with morphine may prevent or delay the development of morphine tolerance in a rat model of bone cancer pain. - The regulation of opioid receptor expression in the PAG and spinal cord may be part of the mechanism.. - Keywords: Dezocine, Tolerance, Morphine, Opioid receptors, Bone cancer pain. - The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. - If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. - However, there have been few reports on the analgesic effect and analgesic tolerance of dezo- cine alone or in combination with opioid agents in the treatment of cancer pain. - In the mechanism research of analgesic effects and tolerance of opioid drugs, it is still very important to study opioid receptors in various parts of brain, including the types and expression of recep- tors, interactions between receptors and receptor genes [12–14]. - animal care of the Cancer Hospital, Chinese Academy of Medical Sciences (No. - Rat model of tibial bone cancer pain. - Rats in the BCP group were anesthetized with pentobarbital (65 mg/kg) and tied in the supine position. - A small incision was made in the lower 1/3 of the left tibia. - After injection, the needle was left in the bone marrow cavity for 2 min and then pulled out. - The hole was closed with bone wax, the wound was cleaned and sutured, and the rats were placed back in the cages.. - The increase in the time to 8 – 16 s suggested that the model was successfully developed and could be used for experiments [10, 16].. - mu opioid receptor (MOR) primer:. - The chemiluminescence method was as follows: ECL hypersensitive luminescent solutions A and B were used, and A and B were mixed in the same volume, incubated with the membrane, and reacted in the dark for 1 min. - Quantification analysis of the blots was performed using ImageJ software. - Data are expressed as the mean ± standard error of the mean. - Bone cancer pain model. - Compared with that of the control group, the defense time in the sham-operated group in- creased significantly from day 1 after surgery (P <. - However, in the BCP group, the defense time was prolonged over time, and there were significant differences compared with the sham group from day 5 (P <. - To measure the analgesic response of opioids in the rats with BCP, we recorded PWL under thermal in- jury over a 7-day period. - There were no significant differences in the PWL baseline between different treatment groups.. - 1 Establishment of a bone cancer pain model. - Behavioral tests of nociception in the groups. - BCP: bone cancer pain. - Pathological examination (H&E staining) of ipsilateral bone tissues in the rats in the BCP group. - 2 Comparison of the thermal nociceptive thresholds among the groups. - produced a significant increase in the thermal noci- ceptive threshold compared with that of the control group (P <. - In contrast, high-dose dezo- cine coadministered with morphine (MD1 group) had a negative effect on the analgesic effect of morphine, and there was no significant difference in the thermal noci- ceptive threshold on day 4 of drug administration com- pared with that of the control group.. - Changes in opioid receptors in the PAG. - The mRNA data were determined by the 2 –ΔΔCT method to estimate the expression of opioid receptors in the PAG relative to that in the control group. - 3C) in the PAG. - Furthermore, there were no significant changes in opioid receptor ex- pression in the D1 or D2 groups. - Dezocine coadminis- tered with morphine (MD1 and MD2 groups) alleviated the morphine-induced downregulation of MOR expres- sion, especially in the MD2 group (Fig. - To investigate the changes in protein levels, we per- formed western blot analyses of opioid receptors in the PAG of the different groups. - In contrast to the findings from the transcriptional analysis, repeated morphine ad- ministration resulted in decreased MOR and DOR pro- tein expression in the PAG (Fig. - In addition, when compared with that in the other groups, KOR expression was significantly reduced in the MD2 group (Fig. - Changes in opioid receptors in the spinal cord. - At the mRNA and protein levels, we observed that a 7- day period of morphine administration upregulated the expression of MOR, KOR and DOR in the spinal cord. - The MD2 group also showed significantly inhibited KOR expression in the spinal cord, similar to the PAG (Fig. - The present study demonstrated that the analgesic effect of morphine was significantly decreased after 4 days of administration, indicating that tolerance was successfully induced after repeated morphine administration in the BCP rat model. - Opioid recep- tor expression in the PAG and spinal cord showed dif- ferent changes in different groups after treatment with morphine alone or in combination with dezocine. - The most significant change was that low-dose dezocine coadministered with morphine significantly reversed morphine-induced downregulation of the expression of MORs and DORs in the PAG and upregulation of the expression of KORs and DORs in the spinal cord. - In the present study, rats in the BCP group showed a significantly prolonged defense time from day 5 com- pared with rats in the control group, suggesting that a rat model of bone cancer pain had been successfully de- veloped. - In recent years, multimodal an- algesia has been widely accepted and used in the treat- ment of bone cancer pain [13]. - 3 The mRNA and protein levels of opioid receptors in the PAG among the different groups. - 4 The mRNA and protein levels of opioid receptors in the spinal cords among the different groups. - Our study found that the expression of MORs decreased in the PAG but increased in the spinal cord after morphine treatment. - Dezocine combined with morphine could have a pro- nounced effect in the PAG but barely showed effects in the spinal cord on the regulation of MORs. - KOR is expressed in the peripheral nerves, dorsal root ganglia, spinal cord, and supraspinal regions and is closely re- lated to pain regulation. - KOR plays an important role in the analgesic effects and tolerance of opioids. - In the present study, KOR mRNA and protein expression was lowest in the groups, and morphine tol- erance developed relatively late in the low-dose dezocine plus morphine group, suggesting that low-dose dezocine may delay the development of morphine tolerance.. - In the bone cancer pain model, the levels of MOR in pain-. - The upregulation of MOR and DOR expression in the PAG and downregulation of KOR expression in the PAG and spinal cord may be part of the mechanisms. - Tao Yan, Guo-hua Zhang and Li Sun contributed to the final revision of the manuscript. - The study was approved by the ethics committee for animal care of the Cancer Hospital, Chinese Academy of Medical Sciences (No. - doi.org/10.2217/fon-2016-0423.. - https://doi.org/10.1016/j.jpain . - https://doi.org/10.1111/aas.12560.. - https://doi.org/1 0.1053/j.jvca . - https://doi.org/10.1213/ANE . - https://doi.. - https://doi.org/10.1021/cn9000236.. - https://doi.org/10.1007/s . - https://doi.org/10.1371/journal.pone.0233412.. - Mu-opioid receptor mRNA regulation during morphine tolerance in the rat peripheral nervous system. - The kappa-opioid receptor is upregulated in the spinal cord and locus ceruleus but downregulated in the dorsal root ganglia of morphine tolerant rats. - https://doi.org/10.1016/j.brainres . - https://doi.org/10.1016/j.neuropharm . - Involvement of chemokine CXCL11 in the development of morphine tolerance in rats with cancer-induced bone pain. - Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord. - https://doi.org . - https://doi.org/1 0.1186/s . - https://doi.org/10.7150/ijms.12616.. - Pathophysiology of bone cancer pain. - https://doi.org/10.1016/j.ejca . - https://doi.org/10.1016/j.urology . - Bone cancer pain: from mechanism to therapy. - https://doi.org/10.1097/SPC.. - Evaluation of bone Cancer pain induced by different doses of Walker 256 mammary gland carcinoma cells. - https://doi.org/10.2147/DDDT.S270478.. - https://doi.org S.. - Discriminative stimulus effects of the mixed-opioid agonist/. - An examination of the interactions between the antinociceptive effects of morphine and various mu-opioids: the role of intrinsic efficacy and stimulus intensity. - https://doi.org/1 0.1213/ANE . - https://doi.org/10.1097/ALN . - Modulation of morphine-induced sensitization by endogenous kappa opioid systems in the rat. - https://doi.org J.. - https://doi.org/10.1124/mol.58.. - https://doi.org/10.103 8/sj.bjp.0705401.. - Down-regulation of mu opioid receptor expression within distinct subpopulations of dorsal root ganglion neurons in a murine model of bone cancer pain.. - https://doi.org/10.1016/j.neuroscience . - Differential activation of the μ -opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model. - https://doi.org/10.1111/j x.. - https://doi.org/10.1126/science.1 060952.
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