Morphine increases metastatic tumor growth

doi:10.1016/0361-9230(86)90057-2

Brain Research Bulletin

Volume 16, Issue 3, March 1986, Pages 363-367

https://doi.org/10.1016/0361-9230(86)90057-2 Get rights and content

Abstract

Walker 256 carcinosarcoma cells produce subpleural pulmonary metastases when given intravenously to the Sprague-Dawley rat. The number of metastases increases when the rat is given morphine subsequent to the tumor load. The increase in the number of mestastases can be blocked be pretreatment with the opiate antagonist naloxone. Naloxone itself does not influence the number of metastases. Pentazocine is an opiate that is agonistic to the endorphin κ-type opiate receptor and partially antagonistic to the μ-type receptor, where morphine acts primarily. While pentazocine alone has no influence on metastases and may decrease the number when given early, pentazocine partially blocks the metastatic inducing effect of morphine.

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Cited by (33)

Drugs of anaesthesia and cancer
2010, Surgical Oncology
Citation Excerpt :
The effects of this drug on tumour growth and metastasis have been investigated. Simon and Arbo demonstrated that in rats, the use of morphine produces an increase in metastatic growth [98]. On the contrary, Yeager and Colacchio demonstrated in vivo, that injections of morphine may decrease the growth of tumour cells that gain access to the circulation during a surgical procedure [99].
Anaesthesia represents one of the most important medical advances in history, and, nowadays, can widely be considered safe, thanks to the discovery of new drugs and the adoption of modern technologies. Nevertheless, anaesthetic practices still represent cause for concern regarding the consequences they produce. Various anaesthetics are frequently used without knowing their effects on specific diseases: despite having been reported that invasion or metastasis of cancer cells easily occurs during surgical procedures, numerous anaesthetics are used for cancer resection even if their effect on the behaviour of cancer cells is unclear.
Guidelines for a proper use of anaesthetics in cancer surgery are not available, therefore, the aim of the present review is to survey available up-to-date information on the effects of the most used drugs in anaesthesia (volatile and intravenous anaesthetics, nitrous oxide, opioids, local anaesthetics and neuromuscular blocking drugs) in correlation to cancer. This kind of knowledge could be a basic valuable support to improve anaesthesia performance and patient safety.
Yohimbine prevents the effect of morphine on the redox status of neuroblastoma × glioma NG108-15 cells
2009, Toxicology Letters
The α₂-adrenoceptor antagonist yohimbine is known to interact with the effects of opioid receptor agonists in vivo, and thus could modulate the action of morphine-like analgesics. The focus of the present work was to further study these interactions in a cell culture endowed with opioid and α₂-adrenoceptors in order to know if they could happen at the cellular level. In a first step, incubation with morphine (10 μM) or the δ opioid agonist DPDPE (1 μM) for 6 h was shown to decrease the reduction of (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) by NG108-15 neuroblastoma × glioma hybrid cells in a naloxone-sensitive manner, thus showing that the opioids affect the redox status of the cells in a δ receptor-mediated way. Further experiments with 2–24 h incubation periods were subsequently performed with morphine 0.1 μM, 10 μM and 1 mM and several tests to confirm the effects on metabolism (MTT, Alamar Blue tests) to examine the potential toxic consequences (neutral red test, trypan blue exclusion assay, LDH test, caspase 3/7 activity) and to study the potential effect of yohimbine on morphine toxicity. These studies confirmed that incubation with morphine (0.1 μM and 10 μM) affected to a similar extent the redox status of the cells, an effect that did not translated into significant cell death and was transient since completely disappeared after 24 h of incubation. Morphine 1 mM was much more toxic than the lower concentrations. Yohimbine effectively prevented the effects of the lower concentrations of morphine when added to the incubation medium at 10 μM, a concentration devoid of significant toxicity. It seems that the exposure to pharmacologically relevant concentrations of morphine gives rise to short-term metabolic alterations of NG108-15 cells mediated by δ receptors and also sensitive to α₂-adrenoceptor blockade; therefore, the interactions previously described in vivo between opioid and α₂-adrenoceptor ligands do not necessarily require the presence of functional neuronal networks and they could happen at the cellular level.
Morphine treatment accelerates sarcoma-induced bone pain, bone loss, and spontaneous fracture in a murine model of bone cancer
2007, Pain
Metastatic bone cancer causes severe pain that is primarily treated with opioids. A model of bone cancer pain in which the progression of cancer pain and bone destruction is tightly controlled was used to evaluate the effects of sustained morphine treatment. In cancer-treated mice, morphine enhanced, rather than diminished, spontaneous, and evoked pain; these effects were dose-dependent and naloxone-sensitive. SP and CGRP positive DRG cells did not differ between sarcoma or control mice, but were increased following morphine in both groups. Morphine increased ATF-3 expression only in DRG cells of sarcoma mice. Morphine did not alter tumor growth in vitro or tumor burden in vivo but accelerated sarcoma-induced bone destruction and doubled the incidence of spontaneous fracture in a dose- and naloxone-sensitive manner. Morphine increased osteoclast activity and upregulated IL-1β within the femurs of sarcoma-treated mice suggesting enhancement of sarcoma-induced osteolysis. These results indicate that sustained morphine increases pain, osteolysis, bone loss, and spontaneous fracture, as well as markers of neuronal damage in DRG cells and expression of pro-inflammatory cytokines. Morphine treatment may result in “add-on” mechanisms of pain beyond those engaged by sarcoma alone. While it is not known whether the present findings in this model of osteolytic sarcoma will generalize to other cancers or opioids, the data suggest a need for increased understanding of neurobiological consequences of prolonged opioid exposure which may allow improvements in the use of opiates in the effective management of cancer pain.
Immunologic effects of opioids in the presence or absence of pain
2005, Journal of Pain and Symptom Management
Citation Excerpt :
However, whether these statistical differences are predictive of changes in disease susceptibility or sensitization to a novel antigen has been shown in only a few animal studies. A single dose of morphine, 5 mg/kg, following the injection of Walker 256 carcinoma cells resulted in a naloxone-reversible increase in metastasis in rats.17 Lockwood et al. tested a range of morphine doses on in vivo antibody responses in an outbred versus an inbred rat strain, and showed dose-related differences in responses to the morphine within strain, as well as differing responses between strains, a complicated picture.18
Opioids are acknowledged to suppress immune functions following both acute and chronic administration; however, there appear to be differences according to the schedule of administration as well as the state of the organism. For example, whereas a single dose of morphine in the absence of pain is well known to be immune suppressive, the biologic consequences of this suppression are largely unknown. Repeated and chronic opioid ingestion in the absence of pain appears to result in significant consequences including high infectious disease prevalence. On the other hand, in the presence of acute pain, there is evidence that opioid administration in analgesic doses is protective. Much less is known regarding the immune and disease implications related to chronic opioid treatment for chronic pain states.
The role of lgl/nk cells in surgery-induced promotion of metastasis and its attenuation by morphine
1994, Brain Behavior and Immunity
Painful stress such as surgery has been shown both to suppress immune function and to promote metastasis, although the degree to which alterations in immunity underlies the tumor-enhancing effects of surgery remains unclear. We recently reported that an experimental laparotomy results in a twofold increase in the number of lung metastases following iv injection of MADB 106 tumor cells, a natural killer (NK)-sensitive mammary adenocarcinoma cell line, syngeneic to the Fischer 344 rats we studied, Further, the administration of an analgesic dose of morphine prevented these metastatic-enhancing effects of surgery. The aim of the present study was to investigate the role of NK cells in both the metastatic-enhancing effects of surgery and the attenuation of these effects by morphine. Using a simple 2 × 2 experimental design (surgery with anesthesia vs anesthesia only, and morphine vs vehicle), we found that surgery resulted in a decrease in both whole blood NK cytotoxic activity and number of circulating LGL/NK cells assessed 4 h postoperatively. In a second experiment involving an 18-h lung clearance assay, we used the mAb 3.2.3 to deplete rats of LGL/NK cells with the following rationale: if LGL/NK cells are necessary to mediate an event, then in their absence, that event should not occur. Normal and LGL/NK-depleted animals were assigned to the same four experimental groups, and radiolabeled MADB 106 tumor cells were injected iv 4 h after surgery. In normal animals, there was a significant interaction between surgery and morphine such that morphine attenuated the surgery-induced increase in tumor cell retention without affecting tumor cell retention in the anesthesia groups. In the LGL/NK-depleted animals, however, although the tumor-enhancing effects of surgery remained evident, morphine did not mitigate this outcome. These results suggest that: (a) both LGL/NK cell activity and other factors independent of LGL/NK cells play a role in the surgery-induced increase in tumor cell retention; and (b) LGL/NK cells play a critical role in morphine′s attenuating effects on this outcome. Finally, these results reinforce concern about the pathogenic consequences of unrelieved pain.
Opium alkaloids, biosynthesis, pharmacology and association with cancer occurrence
2023, Open Biology

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^☆: This work supported by NIH Grant 5 R23 NS17725-02.

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Morphine increases metastatic tumor growth☆

Abstract

Life Sci

Eur J Pharmacol

Eur J Pharmacol

Natl Immunol Cell Growth Regul

Pain

Life Sci

Life Sci

Brain Res Bull

Brain Res Bull

Life Sci

Opiate antagonists can inhibit mammary tumor growth in rats

Opiate and stimulus-produced analgesia: functional anatomy of a medullospinal pathway

The relationship of pharmokinetics to pharmacological activity: morphine, methadone and naloxone

Clin Pharmacokinet