Opium (Taryak) Detoxification impact on Dendritic Cell Dynamics in Chronic Opium Addicts

Background and aim: Evidence suggests that opioid abuse may exert adverse immunomodulatory effects on innate and adaptive immune responses. This research aimed to understand the impact of opioids and their detoxification on the percentage of dendritic cells (DCs) in opium addicts. Material and methods: In this study, 38 chronic opium addicts were divided into two groups. One group received methadone, while the other was treated with buprenorphine. Flow cytometry was employed to analyze dendritic cell subsets including, CD11c+ myeloid dendritic cells and CD123+ plasmacytoid dendritic cells, and surface marker expression including, HLA-DR, CD11c, CD123. Results: A significant difference was observed in the percentages of peripheral blood myeloid DCs between the addicted subjects and the control group. However, no significant change was noted in the percentage of plasmacytoid DCs between the two groups. Detoxification with methadone exacerbated the reduction of myeloid DCs in the peripheral blood of addicts, whereas the buprenorphine detoxification regimen appeared to correct this decrease. Conclusion: Dendritic cells play a crucial role in both innate and adaptive immune responses. Thus, the impairment caused by opium in these cells could increase the occurrence of infectious diseases. The findings suggest that buprenorphine may be advantageous in ameliorating the immunological disorders associated with opium abuse. Opium (Taryak) Detoxification impact on Dendritic Cell Dynamics in Chronic Opium Addicts Ghasem Mosayebi, 1,2, Seyed Mohammad Moazzeni, 3, Hadiseh Farahani 1, Hassan Solhi 4, Mohammad Rafiei 5, Shirin Fateh 3, Ali Ghazavi 1,6,7 * 1 Department of Immunology, School of Medicine, Arak University of Medical Sciences, Arak, Iran 2 Molecular and Medicine Research Center, Arak University of Medical Sciences, Arak, Iran 3 Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran 4 Department of Clinical Toxicology and Forensic Medicine, Arak University of Medical Sciences, Arak, Iran 5 Department of Biostatistics, School of Medicine, Arak University of Medical Sciences, Arak, Iran 6 Traditional and Complementary Medicine Research Center (TCMRC), Arak University of Medical Sciences, Arak, Iran 7 Infectious Diseases Research Center (IDRC), Arak University of Medical Sciences, Arak, Iran Corresponding author: E-mail: [email protected] Tel: +98 86 33838185 Fax: +98 86 34173526 ORCID: 0000-0002-4219-9594 P.O. Box: 38195-1884 Postal Code: 38481-7-6941

Background and aim: Evidence suggests that opioid abuse may exert adverse immunomodulatory effects on innate and adaptive immune responses. This research aimed to understand the impact of opioids and their detoxification on the percentage of dendritic cells (DCs) in opium addicts.

In this study, 38 chronic opium addicts were divided into two groups. One group received methadone, while the other was treated with buprenorphine. Flow cytometry was employed to analyze dendritic cell subsets including, CD11c+ myeloid dendritic cells and CD123+ plasmacytoid dendritic cells, and surface marker expression including, HLA-DR, CD11c, CD123.

A significant difference was observed in the percentages of peripheral blood myeloid DCs between the addicted subjects and the control group. However, no significant change was noted in the percentage of plasmacytoid DCs between the two groups. Detoxification with methadone exacerbated the reduction of myeloid DCs in the peripheral blood of addicts, whereas the buprenorphine detoxification regimen appeared to correct this decrease.

Dendritic cells play a crucial role in both innate and adaptive immune responses. Thus, the impairment caused by opium in these cells could increase the occurrence of infectious diseases. The findings suggest that buprenorphine may be advantageous in ameliorating the immunological disorders associated with opium abuse. Key Words: Dendritic cells, Buprenorphine, Methadone, Opium, Taryak, Detoxification.

Substance abuse, on a universal scale, substantially negatively impacts the economy and the social aspects of communities. Additionally, studies carried out on humans and animals, as well as laboratory conditions, have shown that opioid abuse has a destructive impact on the body’s immune system and modulates both innate and adaptive immune responses (1, 2). Narcotics can increase the risk of infectious diseases such as bacterial pneumonia, urinary tract infections, and tuberculosis. They also provide suitable conditions for these diseases to increase in severity and become chronic. Additionally, drug abuse can lead to a higher risk of developing several types of cancer (3). Opioids are synthetic or natural substances with effects similar to Taryak or morphine, exerting their influence on the central nervous system, autocrine, and immune systems through their receptors (4). Narcotics affect various body systems through four different types of receptors, including μ receptor (MOR), κ receptor (KOR), δ receptor (DOR), and σ receptor (SOR). These receptors have varying affinity, distribution, and function according to ligands (5). Methadone and buprenorphine are used to facilitate the discontinuation of drug use and aid in detoxifying the effects of Taryak (6). There is an increasing understanding that methadone and buprenorphine have diverse effects on innate and adaptive immunity (7). Researchers have mainly focused on studying the immunomodulatory effects of various materials on lymphocytes, which are the primary cell targets. However, recent evidence has shown that immunomodulatory substances exert their effects by suppressing dendritic cells’ differentiation, maturation, and activity (8). The human dendritic cells (hDCs) population is diverse and comprises about 1% of the mononuclear cells in circulating blood. hDCs are antigen-presenting cells lacking leukocyte antigens (CD3, CD14, CD16, CD19, CD20, and CD56) (9) .hDCs respond to a broad spectrum of bacterial, viral, parasitic, and tumor pathogens (10). Dendritic cells are highly effective antigen-presenting cells (APCs). They are capable of activating naive T lymphocytes and play a critical role in initiating and regulating the immune response (11). Some key features include their different subtypes, strategic distribution in the body, and expression of various receptors that allow them to respond to different stimuli (12). The human body contains various dendritic cells, categorized into two main groups: CD11c+ myeloid dendritic cells (mDC) and CD123+ plasmacytoid dendritic cells (pDC) (13). The majority of experiments involving opioids have been conducted on patients who were given these drugs for pain relief after surgery or to manage severe pain (14). Only a few of these studies examined the direct effects of opioids on the immune system in cases where there was no surgery, pain, or tissue damage (15). Therefore, further research is necessary to understand the effects of opioids on the immune system. This study investigated the immunomodulatory effects of Taryak and detoxifier treatments on dendritic cells.

The study was conducted in accordance with the Basic & Clinical Pharmacology & Toxicology policy for experimental and clinical studies (16). Participants : A group of 40 control subjects was selected from university staff and students who had never used psychotropic drugs. The general health of the control group was confirmed through a physical examination of each individual and by conducting routine biochemistry and hematology tests. The Ethics Committee approved the study, and all participants provided their consent. The control group was closely matched with the addicted group in terms of age, sex, weight, height, and body mass index (BMI). All volunteers aged 20 to 40 were free of infectious, inflammatory, and other diseases affecting the immune system. Urine samples from the control group tested negative for morphine use. Individuals who consumed over 2 grams of opium daily for more than a year, without using other drugs for longer than 3 months in the past and without being alcoholic for more than 6 months previously, and whose urine test showed more than 5.5 μg/ml of morphine were chosen as the addicted group. Sample selection, treatment, and sampling: A urine sample was collected from all the participants to measure the 10 most commonly used drugs. The urine samples from the control group were collected one month before the study and then again at the beginning of the study. The urine samples from the addicts were collected and checked weekly. A urine sample was also obtained at the final blood sampling stage one month after the detoxification program ended for the conclusive test. The presence of drugs was identified using a test strip. Serology tests were performed on the participants’ blood samples to detect antibodies against HBV, HCV, and HIV. Positive cases were excluded from the study. A total of 38 addicts were split into two groups. One group received methadone treatment, while the other was treated with buprenorphine. The methadone group was given 20 to 40 mg of methadone chloride syrup orally each day. In comparison, the buprenorphine group received 12 mg of buprenorphine tablets daily, with the dosage eventually tapered down to zero. The immune response of the addicted group was assessed at three different times: at the start of the trial, at the end of detoxification (28 to 35 days after treatment, during Therapeutic Remission), and at the most one month after the end of detoxification (before the onset of withdrawal symptoms). Blood samples for Therapeutic Remission were collected one hour after taking the detoxifier. Determination of frequency of peripheral blood CD11c + and CD123 + dendritic cells 5 ml of peripheral blood with 1000 IU/ml heparin was diluted in a 2:1 ratio and then subjected to Ficoll density gradient centrifugation at 600 × g for 20 minutes at 4°C. Peripheral blood mononuclear cells were meticulously collected from the interface between the plasma and the Ficoll layer. The resulting pellets were resuspended, cells were counted using a hemocytometer, and their viability rate was measured (viability should be above 90% to ensure the accuracy of dendritic cell counts). Adding FACS buffer achieved a concentration of 25 × 10⁶ cells/ml. Subsequently, 20 μl of this concentration (equivalent to 5 × 10⁵ cells) was transferred to the FACS tube. Then, 15 μl of Lin-1 cocktail (Anti-CD3, CD14, CD16, CD19, CD20, CD16, CD19, CD20, CD56) labeled with FITC, 5 μl anti-CD34 labeled with FITC (to remove CD34 + HLA-DR + precursors), and 5 μl antibodies against HLA-DR labeled with PerCP were added to each tube. For a three-color flow cytometry analysis to determine the number of Lin- / HLA-DR +/ CD123 + DCs (pDC), 5 μl of PE-labeled CD123 antibody was added to a tube. Additionally, 5 μl of PE-labeled anti-CD11c antibody was used for a three-color flow cytometry analysis to determine the number of Liner- / HLA-DR + / CD11c + dendritic cells (mDC). The samples were then analyzed using FACScan flow cytometry (BD Biosciences, San Jose, CA), and the data were processed using FlowJo software (17). Statistical analysis: One-way analysis of variance (ANOVA) was employed to assess statistical significance between experimental groups. Post-hoc tests were performed using Tukey’s HSD (Honestly Significant Difference) test to determine specific group differences when ANOVA indicated significant effects. All data are presented as mean ± SEM. P-values < 0.05 were considered statistically significant (*p < 0.05, **p < 0.01). 1-Selection of volunteers There was no statistically significant difference in age, height, weight, and BMI between the two group (Table 1). The control group’s general health was evaluated through a physical exam and a routine hematological and biochemistry test. According to the mentioned selection criteria, 40 healthy individuals and 38 addicts were chosen to take part in a control group and an experiment group, respectively. | (Mean of years ± SD) \RL Age | 35.6 ± 0.61 | 33.5 ± 62.04 | 0.634 | | (Mean of cm ± SD) \RL Height | 174.6 ± 50.36 | 175.6 ± 12.89 | 0.844 | | (Mean of kg ± SD) \RL Weight | 74.13 ± 30.67 | 74.4 ± 20.50 | 0.954 | | Body Mass Index (Mean ± SD) | 24.3 ± 35.96 | 24.1 ± 16.41 | 0.90 | Table 1: Demographic characteristics of participants in the study 2- Determination of dendritic cell count in volunteers’ peripheral blood In this study, dendritic cells were defined as Lin-HLA-DR+cells, and the percentage of either kind of dendritic cell (CD11c+ and CD123 + ) was calculated at the gate of single-nucleotide cells. Fig. 1. Phenotype of peripheral blood dendritic cells in healthy subjects. The PBMC (peripheral blood mononuclear cell) population is identified by a combination of forward/side scatter characteristics (a), and PBDCs (peripheral blood dendritic cells ) were identified within the lineage (CD3, CD14, CD16, CD19, CD20, CD56, and CD34)-negative (Lin−) HLA-DR+ (b). One representative experiment demonstrates the gating strategy for identifying DC subsets. pDCs: plasmacytoid DCs (CD123+) (c), mDCs: myeloid DCs (CD11c+) (d). As shown in Fig. 2a, the number of leukocytes per microliter of peripheral blood of opium addicts was significantly increased when compared to the control group. On the same way, the number of mononuclear (lymphocyte + monocyte) cells of opium addicts was also considerably higher than that of the control group (Fig. 2b). To calculate the percentage of dendritic cells, 100000 cells were counted. The percentage of peripheral blood dendritic cells in opium addicts was lower than in the control group. However, it was not significant (Fig. 2c). Fig. 2. The number of circulating leukocytes (a), mononuclear cell (b), and the percentage of dendritic cells (c) in peripheral blood. WBC = leukocyte, PBMC = peripheral blood mononuclear cells, DC = dendritic cell, Ctrl = control, Opi = opium. Data are presented as mean ± standard error. The * symbol indicates P<0.005, and the ** symbol indicates P<0.0005 compared to the control. Fig. 3a shows that the percentage of CD11c+ dendritic cells in opium addicts’ peripheral blood was significantly lower than that of the control group. Howevr, the number of CD123+ dendritic cells in the peripheral blood of opium addicts was found to be similar to that of controls, as depicted in Fig. 3b. Fig. 3. The percentage of CD11c+ (a) and CD123+ (b) dendritic cells in peripheral blood. Ctrl= control, Opi= opium, DC = dendritic cell . Data are presented as mean ± standard error. The results were extracted from the analysis of 100 thousand mononuclear cells. * indicates P<0.005 compared to control. The Immune response of the addicted group was evaluated in three separate periods, including the beginning of the trial, the end of detoxification (28 to 35 days after treatment, Therapeutic Remission), and a maximum of one month after the end of detoxification (before the onset of withdrawal symptoms). Taryak addicted group was divided into two treatment groups (Methadone and Buprenorphine). As shown in Fig. 4, the increased number of leukocytes per microliter of peripheral blood of opium addicts during methadone detoxification and buprenorphine was not significant in comparison with the control group. Fig. 4. The number of circulating leukocytes of opium addicts during the detoxification period WBC = leukocyte, Ctrl = control, MetOpi = opiate addicts treated with methadone, BpnOpi = opiate addicts treated with buprenorphine, a = at entry, b = end of detoxification period, c = maximum one month after detoxification period. Data are presented as mean ± standard error. On the other hand, the number of mononuclear cells (lymphocytes + monocytes) per microliter of peripheral blood in opium addicts during the detoxification period with methadone and buprenorphine showed a statistically significant increase compared to the control group (Fig. 5). Fig. 5. The number of circulating mononuclear cells of opiate addicts during the detoxification period. PBMC = peripheral blood mononuclear cells, Ctrl = control, MetOpi = opiate addicts treated with methadone, BpnOpi = opiate addicts treated with buprenorphine, a= upon arrival, b= the end of the detoxification period, c= maximum one month after the detoxification period. Data are presented as mean ± standard error. * indicates P<0.05, ** indicates P<0.005, and ***indicates P<0.0005 compared to the control. Detoxification by methadone significantly reduced the percentage of peripheral blood dendritic cells in opium addicts compared to the control group. In contrast, buprenorphine treatment substantially increased DCs (Fig. 6). Fig. 6. The percentage of dendritic cells in the peripheral blood of opium addicts during the detoxification period. DC = dendritic cell, Ctrl = control, MetOpi = opiate addicts treated with methadone, BpnOpi = opiate addicts treated with buprenorphine, a = at entry, b = end of detoxification period, c = maximum one month after detox period removal Data are presented as mean ± standard error. * indicates P<0.05, ** indicates P<0.005, and *** indicates P<0.0005 compared to the control. Methadone detoxification significantly reduced the percentage of CD11c+DCs compared to the control group. While buprenorphine detoxification notably upregulated the percentage of CD11c+ DCs in the peripheral blood of opium addicts (Fig. 7). Fig. 7.The percentage of peripheral blood CD11c+ dendritic cells of opium addicts during the detoxification period. Ctrl= control, MetOpi= opiate addicts treated with methadone, BpnOpi= opiate addicts treated with buprenorphine, a= at entry, b= end of detoxification period, c= up to one month after detoxification period. Data are presented as mean ± standard error. The results were extracted from the analysis of 100 thousand mononuclear cells. * indicates P<0.05, ** indicates P<0.005, and *** indicates P<0.0005 compared to the control. Fig.8 illustrates that CD123+ DCs percentage in the peripheral blood of Taryak addicts who received methadone treatment did not change compared to the control group. Although buprenorphine detoxification slightly elevated the percentage of CD123+ DCs in peripheral blood samples of opium addicts, this rise was not statistically meaningful. Fig. 8. The percentage of peripheral blood CD123+ dendritic cells of opium addicts during the detoxification period. Ctrl = control, MetOpi = opium addicts treated with methadone, BpnOpi = opium addicts treated with buprenorphine, a = at entry, b = end of detoxification period, c = maximum one month after the detoxification period. Data are presented as mean ± standard error. The results were extracted from the analysis of 100 thousand mononuclear cells. * indicates P<0.05, ** indicates P<0.005, and *** indicates P<0.0005 compared to the control.

Dendritic cells are very effective in antigen processing and presenting; these cells are programmed to stimulate naïve T cells and regulate the subsequent immune response. Their different subtypes are scattered throughout the body. Dendritic cells are primarily categorized into CD11c+ and CD123+ groups, which differ in cytokine production profile, maturation, and survival processes. New dendritic cells produced in the bone marrow migrate via the bloodstream to various peripheral tissues (18). Therefore, circulating DCs could indicate the status of the immune system. For instance, the Lissoni et al. study showed a correlation between a decrease in circulating DCs number and a suppressive state of the immune system in malignant metastatic cancer patients (19). Various pathogens may activate a different subset of dendritic cells, and the activation of these subsets depends on the stages of the immune response (20). Myeloid dendritic cells are believed to stimulate the cellular immune response by promoting the development of TH1 (T helper-1) cells. In contrast, plasmacytoid DCs encourage the production of antibodies by induction of the TH2 (T helper-2) response. The ratio of myeloid DCs to plasmacytoid DCs may serve as a valuable indicator of immune status (21). Drugs show their immunomodulatory capability through the increased susceptibility to infections and the severity of these diseases in drug addicts (7). Increased incidence of a variety of cancers in addicts is another sign of the immunomodulation effects of narcotics (22). Drugs have receptors in different body systems through which they apply their influence (23). In this study, we measured the total percentage of DCs and their two central subtypes in the peripheral blood of drug addicts. We observed a significant increase in the number of leukocytes and mononuclear cells (lymphocyte + monocyte) in the peripheral blood of Trayak addicts. Consistent with our results, Govitrapong et al. experimented on 19 heroin addicts, 17 recovered addicts, and 17 healthy people, which showed that the total number of B and T lymphocytes was higher in heroin addicts (24). Growth in leukocytes and mononuclear cell count could result from their higher production or release rate of bone marrow; the other possible reason could be the lower migration rate toward inflammation sites (25). In line with our results, Clark et al. demonstrated in a mouse model that morphine prevents neutrophil infiltration to inflamed areas (26). Research on the mice model by Martin et al. suggests that chronic morphine misuse resulted in the inhibition of neutrophil chemotaxis, which led to delayed wound healing (27). Miyagi et al. added morphine to the culture medium of rhesus monkey leukocytes and observed that leukocyte chemotaxis towards the RANTES chemokine was reduced (28). In the study of Yossuck et al., morphine interfered with infants’ neutrophils chemotaxis to IL-8 (29). In our study, opium significantly reduced the percentage of CD11c+ DCs in the peripheral blood of addicts. (30). Our previous study on heroin addicts demonstrated that CD11c+ dendritic cells in heroin addicts were significantly lower than healthy controls (17). This reduction could occur due to changes in the production of DC precursors in bone marrow, or it could be due to an impairment in monocytes’ reaction to differentiating factors and inhibition of these factors. Another possible reason is induced apoptosis in dendritic cells (31). Human monocytes could be differentiated into DCs or macrophages. The presence of stimuli such as GM-CSF and IL-4 in the monocyte microenvironment differentiates them from dendritic cells (32, 33). Roy et al. also reported an impairment in the response of morphine-treated mice monocytes to M-CSF stimulants in the medium, which was reversible with naloxone. Additionally, they showed that chronic morphine consumption in mice inhibited M-CSF in bone marrow (34). Some studies imply that morphine induces apoptosis in macrophages by increasing TGF-β concentration and expressing p38 MAPK, Fas, and Fas L (35). In the study of Weed et al., drinking water containing morphine for several months, monkeys reduced the total count and percentage of NK cells (36). Cited studies focused on morphine; however, we used Taryak in our research. Taryak (opium) has more than 80 distinct alkaloids, comprised of about 25% of its weight. Morphine, with 3-23%, is the largest constituent among opium alkaloids (37). Opium addicts were divided into two treatment groups. The first group was treated with methadone, while the second group was treated with buprenorphine. Immune responses of these groups were evaluated in 3 periods: initiation of the trial, the end of the detoxification, and up until one month after the detoxification. Detoxification with methadone and buprenorphine did not affect the number of peripheral blood leukocytes, while elevated the number of peripheral blood mononuclear cells (lymphocyte + monocyte) compared to the control group. Our results were in line with the Neri et al. study on heroin addicts. In 2005, they conducted research on 62 heroin addicts who were divided into two treatment groups (31 patients with methadone and 31 patients with buprenorphine); the results of this study showed that the number of monocytes in both groups was increased compared to the beginning of treatment (38). Methadone treatment notably reduced the total dendritic cell count and CD11c+dendritic cells, while treatment with buprenorphine showed a reverse effect and modified the reduction of dendritic cells, which was statistically significant. While treatment with methadone decreased the percentage of CD123+ dendritic cells, detoxification with buprenorphine increased the cell count. Nonetheless, these changes were not substantial. According to Ninnemann, methadone directly suppresses human T cell function, and interferes with Treg induction and expansion in vitro (39). Sacerdote et al. revealed that Buprenorphine maintenance therapy restores immune function in heroin addicts (40). \RL \RL

Based on the findings of this study, opium interferes with the development of dendritic cells in addicts. Given the critical role of dendritic cells, this impairment could result in transient immunosuppressive effects on the dendritic cells’ ability to respond to and eliminate pathogens promptly and might increase the incidence of infectious diseases. Our results imply that buprenorphine might be beneficial in modifying immunological disorders caused by opium misuse. Further studies are required to recognize the signal transduction pathways used by these drugs to improve the differentiation and maturation of dendritic cells. Acknowledgments This work was supported by the Research Council of Arak University of Medical Sciences. Funding This study was funded by the Council of Arak University of Medical Sciences (grant number 658). Availability of data and materials The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request. Declarations Conflict of interest The authors declare that there is no conflict of interest. Ethics approval and consent to participate The Ethics Committee of Arak University of Medical Sciences approved this study (Ethical Code: IR.ARAKMU.REC.1390.113.9).

1. Kheirabadi D, Minhas D, Ghaderpanah R, Clauw DJ. Problems with opioids - beyond misuse. Best Practice & Research Clinical Rheumatology. 2024:101935.2. Room R, Cook M, Laslett A-M. Substance use and the Sustainable Development Goals: will development bring greater problems? Drugs: Education, Prevention and Policy. 2024;31(1):148-57.3. Sun Q, Li Z, Wang Z, Wang Q, Qin F, Pan H, et al. Immunosuppression by opioids: Mechanisms of action on innate and adaptive immunity. Biochemical Pharmacology. 2023;209:115417.4. Plein LM, Rittner HL. Opioids and the immune system - friend or foe. British journal of pharmacology. 2018;175(14):2717-25.5. Wang Y, Zhuang Y, DiBerto JF, Zhou XE, Schmitz GP, Yuan Q, et al. Structures of the entire human opioid receptor family. Cell. 2023;186(2):413-27.e17.6. Wu E, El-Bassel N, Gilbert L, Chang M, Sanders G. Effects of receiving additional off-site services on abstinence from illicit drug use among men on methadone: a longitudinal study. Evaluation and Program Planning. 2010;33(4):403-9.7. Abdel Shaheed C, Beardsley J, Day RO, McLachlan AJ. Immunomodulatory effects of pharmaceutical opioids and antipyretic analgesics: Mechanisms and relevance to infection. British Journal of Clinical Pharmacology. 2022;88(7):3114-31.8. Papageorgiou M, Raza A, Fraser S, Nurgali K, Apostolopoulos V. Methamphetamine and its immune-modulating effects. Maturitas. 2019;121:13-21.9. José Luis M-C, Juan Francisco C-C, Oscar G-C, Paola Trinidad V-G, Luis Guillermo R-G, Jazmín Monserrat V-B. Role of Dendritic Cells in Pathogen Infections: A Current Perspective. In: Bhawana S, editor. Cell Interaction. Rijeka: IntechOpen; 2021. p. Ch. 8.10. Antushevich H. Interplays between inflammasomes and viruses, bacteria (pathogenic and probiotic), yeasts and parasites. Immunology Letters. 2020;228:1-14.11. Yin X, Chen S, Eisenbarth SC. Dendritic Cell Regulation of T Helper Cells. Annual Review of Immunology. 2021;39(Volume 39, 2021):759-90.12. Zanna MY, Yasmin AR, Omar AR, Arshad SS, Mariatulqabtiah AR, Nur-Fazila SH, et al. Review of Dendritic Cells, Their Role in Clinical Immunology, and Distribution in Various Animal Species. International journal of molecular sciences. 2021;22(15).13. Soltani S, Mahmoudi M, Farhadi E. Dendritic cells currently under the spotlight; classification and subset based upon new markers. Immunological Investigations. 2021;50(6):646-61.14. Meier IM, Eikemo M, Trøstheim M, Buen K, Jensen E, Gurandsrud Karlsen S, et al. Factors associated with use of opioid rescue medication after surgery. Regional Anesthesia & Pain Medicine. 2024;49(4):265-71.15. Moyano J, Aguirre L. Opioids in the immune system: from experimental studies to clinical practice. Revista da Associacao Medica Brasileira (1992). 2019;65(2):262-9.16. Tveden-Nyborg P, Bergmann TK, Jessen N, Simonsen U, Lykkesfeldt J. BCPT 2023 policy for experimental and clinical studies. Basic & clinical pharmacology & toxicology. 2023;133(4):391-6.17. Akbari A, Mosayebi G, Samiei AR, Ghazavi A. Methadone therapy modulate the dendritic cells of heroin addicts. International immunopharmacology. 2019;66:330-5.18. Tong C, Liang Y, Han X, Zhang Z, Zheng X, Wang S, et al. Research Progress of Dendritic Cell Surface Receptors and Targeting. Biomedicines. 2023;11(6).19. Lissoni P, Vigore L, Ferranti R, Bukovec R, Meregalli S, Mandala M, et al. Circulating dendritic cells in early and advanced cancer patients: diminished percent in the metastatic disease. Journal of biological regulators and homeostatic agents. 1999;13(4):216-9.20. Liu YJ, Kanzler H, Soumelis V, Gilliet M. Dendritic cell lineage, plasticity and cross-regulation. Nature immunology. 2001;2(7):585-9.21. Kunitani H, Shimizu Y, Murata H, Higuchi K, Watanabe A. Phenotypic analysis of circulating and intrahepatic dendritic cell subsets in patients with chronic liver diseases. Journal of hepatology. 2002;36(6):734-41.22. Rashidian H, Zendehdel K, Kamangar F, Malekzadeh R, Haghdoost AA. An Ecological Study of the Association between Opiate Use and Incidence of Cancers. Addiction & health. 2016;8(4):252-60.23. Ciucă Anghel DM, Nițescu GV, Tiron AT, Guțu CM, Baconi DL. Understanding the Mechanisms of Action and Effects of Drugs of Abuse. Molecules (Basel, Switzerland). 2023;28(13).24. Govitrapong P, Suttitum T, Kotchabhakdi N, Uneklabh T. Alterations of immune functions in heroin addicts and heroin withdrawal subjects. The Journal of pharmacology and experimental therapeutics. 1998;286(2):883-9.25. Mank V, Azhar W, Brown K. Leukocytosis. StatPearls. Treasure Island (FL) ineligible companies. Disclosure: Waqas Azhar declares no relevant financial relationships with ineligible companies. Disclosure: Kevin Brown declares no relevant financial relationships with ineligible companies.: StatPearls PublishingCopyright © 2024, StatPearls Publishing LLC.; 2024.26. Clark JD, Shi X, Li X, Qiao Y, Liang D, Angst MS, et al. Morphine reduces local cytokine expression and neutrophil infiltration after incision. Molecular pain. 2007;3:28.27. Martin JL, Koodie L, Krishnan AG, Charboneau R, Barke RA, Roy S. Chronic morphine administration delays wound healing by inhibiting immune cell recruitment to the wound site. The American journal of pathology. 2010;176(2):786-99.28. Miyagi T, Chuang LF, Lam KM, Kung H-f, Wang JM, Osburn BI, et al. Opioids suppress chemokine-mediated migration of monkey neutrophils and monocytes — an instant response. Immunopharmacology. 2000;47(1):53-62.29. Yossuck P, Nightengale BJ, Fortney JE, Gibson LF. Effect of morphine sulfate on neonatal neutrophil chemotaxis. The Clinical journal of pain. 2008;24(1):76-82.30. Liu J, Zhang X, Cheng Y, Cao X. Dendritic cell migration in inflammation and immunity. Cellular & Molecular Immunology. 2021;18(11):2461-71.31. Downes JE, Marshall-Clarke S. Innate immune stimuli modulate bone marrow-derived dendritic cell production in vitro by toll-like receptor-dependent and -independent mechanisms. Immunology. 2010;131(4):513-24.32. Patel AA, Ginhoux F, Yona S. Monocytes, macrophages, dendritic cells and neutrophils: an update on lifespan kinetics in health and disease. Immunology. 2021;163(3):250-61.33. Lellahi SM, Azeem W, Hua Y, Gabriel B, Paulsen Rye K, Reikvam H, et al. GM-CSF, Flt3-L and IL-4 affect viability and function of conventional dendritic cell types 1 and 2. Frontiers in immunology. 2022;13:1058963.34. Roy S, Ramakrishnan S, Loh HH, Lee NM. Chronic morphine treatment selectively suppresses macrophage colony formation in bone marrow. European Journal of Pharmacology. 1991;195(3):359-63.35. Porras A, Zuluaga S, Black E, Valladares A, Alvarez AM, Ambrosino C, et al. p38α Mitogen-activated Protein Kinase Sensitizes Cells to Apoptosis Induced by Different Stimuli. Molecular Biology of the Cell. 2004;15(2):922-33.36. Weed MR, Carruth LM, Adams RJ, Ator NA, Hienz RD. Morphine withdrawal dramatically reduces lymphocytes in morphine-dependent macaques. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology. 2006;1(3):250-9.37. Nakhaee S, Ghasemi S, Karimzadeh K, Zamani N, Alinejad-Mofrad S, Mehrpour O. The effects of opium on the cardiovascular system: a review of side effects, uses, and potential mechanisms. Substance Abuse Treatment, Prevention, and Policy. 2020;15(1):30.38. Neri S, Bruno C, Pulvirenti D, Malaguarnera M, Italiano C, Mauceri B, et al. Randomized clinical trial to compare the effects of methadone and buprenorphine on the immune system in drug abusers. Psychopharmacology. 2005;179:700-4.39. Ninnemann A, Hock K, Luppus S, Scherbaum N, Temme C, Buer J, et al. Direct effects of heroin and methadone on T cell function. International immunopharmacology. 2024;140:112736.40. Sacerdote P, Franchi S, Gerra G, Leccese V, Panerai AE, Somaini L. Buprenorphine and methadone maintenance treatment of heroin addicts preserves immune function. Brain, behavior, and immunity. 2008;22(4):606-13. Information & Authors Information Version history Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Metrics & Citations Metrics Article Usage 204views 113downloads Citations Download citation Ghasem Mosayebi, Seyed Mohammad Moazzeni, Hadiseh Farahani, et al. Opium (Taryak) Detoxification impact on Dendritic Cell Dynamics in Chronic Opium Addicts. Authorea. 09 January 2025. DOI: https://doi.org/10.22541/au.173639558.84194800/v1 DOI: https://doi.org/10.22541/au.173639558.84194800/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.