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British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 2014 Jul 1;172(2):251–259. doi: 10.1111/bph.12589

Comparison and analysis of the animal models used to study the effect of morphine on tumour growth and metastasis

B Afsharimani 1, C W Doornebal 2, P J Cabot 1, M W Hollmann 2, M-O Parat 1
PMCID: PMC4292942  PMID: 24467261

Abstract

The effect of opioids on tumour growth and metastasis has been debated for many years, with recent emphasis on the possibility that they might influence the rate of disease-free survival after tumour resection when used in the perioperative pain management of cancer surgery patients. The literature presents conflicting and inconclusive in vitro and in vivo data about the potential effect of opioids, especially morphine, on tumour growth and metastasis. To inform clinical practice, appropriate animal models are needed to test whether opioids alter the course of tumour growth and metastasis. Here, we review the literature on animal-based studies testing the effect of morphine on cancer so far, and analyse differences between the models used that may explain the discrepancies in published results. Such analysis should elucidate the role of opioids in cancer and help define ideal pre-clinical models to provide definitive answers.

LINKED ARTICLES

This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2

Keywords: morphine, animal models, tumour growth, metastasis

Introduction

Morphine and other opioid analgesics are potent pain-relieving agents that are essential for pain management in cancer patients (Dalal and Bruera, 2013). Besides being the standard of care for the treatment of cancer-related pain in patients with advanced stage disease, opioids – especially morphine – are also routinely used for anaesthetic procedures in cancer patients undergoing surgery. However, there have been concerns that they may affect the rate of post-operative cancer recurrence and metastasis (Afsharimani et al., 2011). Recent retrospective clinical studies evaluating the effects of anaesthetic technique on relapse-free survival after cancer surgery indicated that cancer patients receiving perioperative morphine-based analgesia had a worse prognosis compared with those receiving loco-regional anaesthesia (Exadaktylos et al., 2006; Biki et al., 2008). Based upon these findings, morphine and other opioid analgesics have been postulated to promote cancer progression and relapse (Heaney and Buggy, 2012). Although still rather controversial, these studies collectively raised the question of whether the anaesthetic technique applied during cancer surgery might affect relapse-free survival after surgery (Sessler, 2008; Singleton and Moss, 2010).

To resolve this controversy, several randomized clinical trials in breast, lung and prostate cancer patients have been initiated. These clinical studies are designed to directly compare relapse-free survival after cancer surgery in patients receiving either loco-regional anaesthesia or perioperative morphine-based analgesia. Yet, given their design, these studies will not allow assessment of any potential tumour-promoting effects of morphine-based analgesia. To address this question, we need to rely upon in vivo studies that evaluate the effects of morphine on tumour progression and metastatic disease in a well-controlled experimental setting. In this review, we summarize the currently available data from pre-clinical studies evaluating the effects of morphine on tumour growth and metastatic disease. Interestingly, results from these studies show discrepant results ranging from deleterious, null to protective effects for morphine. This review critically evaluates the models that have been used, in an attempt to elucidate the parameters that may explain these discrepancies and therefore shed some light on the role of morphine in cancer. To support future research, we further discuss some essential characteristics that should be met by pre-clinical models in order to address this question in a clinically relevant setting.

The tumour models used

To evaluate the effects of morphine on tumour progression and metastatic disease, a wide variety of pre-clinical models have been employed. As shown in Table 1, most studies are performed with cancer cell line-based tumour models. In these models, in vitro maintained cancer cell lines are transplanted either orthotopically (in the anatomic location of origin for this specific tumour cell line) or ectopically (in another organ or location), or injected i.v. into hosts. Unfortunately, these models present considerable shortcomings, as they do not faithfully reproduce de novo tumourigenesis and metastatic disease in humans. For example, cancer cell lines, maintained in vitro, often fail to reflect the original heterogeneity of the parental tumour (Keller et al., 2010; Domcke et al., 2013). As intra-tumour heterogeneity corresponds to a wide phenotypic variety and at least partially determines clinically relevant tumour-related features including the ability to seed and responses to therapy (Marusyk et al., 2012), data from such studies cannot easily be extrapolated to the clinical setting.

Table 1.

Studies employing a pre-clinical model to assess the effect of morphine on tumour growth and metastasis

Rodent model Induced pain or surgical stress Dose of morphine Effect of morphine on tumour growth and metastasis Reference
Walker 256 carcinoma cells cultivated in ascites, then injected in Sprague-Dawley rats Immuno-competent rats Ectopic (injection in the tail vein) No 5 mg·kg−1 single i.p. injection at the time of tumour inoculation Increased number of lung metastases Simon and Arbo (1986)
Both syngeneic and allogeneic Immuno-competent mice Ectopic (s.c., i.p.) No 10 mg·kg−1 s.c. once daily for 10 days Promotion of tumour growth Ishikawa et al. (1993)
Syngeneic Immunocompetent rats Injection of tumour cells in ileocecal vein Yes (laparotomy) Morphine sulfate (15 mg·kg−1 4 doses over 24 h perioperatively) Increased tumour burden Colacchio et al. (1994)
Allogeneic Immuno-compromised mice Orthotopic breast tumour No 0.714 mg·kg−1·day−1 s.c. for 2 weeks, followed by 1.43 mg·kg−1·day−1 for 3 weeks Increased tumour volume after 32 days Gupta et al. (2002)
Syngeneic A/J mice are immuno-competent but present a defect in macrophage function Ectopic (s.c. in right hind thigh) Pain increases with tumour growth 0.714 mg·kg−1 day−1 for 7 days followed by 1 mg·kg−1·day−1 for 7 days Morphine non-analgesic Increased tumour weight and presence of metastases Farooqui et al. (2007)
Syngeneic Immuno-competent rats Tail vein injection of tumour cells Yes (laparotomy) 10 mg·kg−1 immediately and 5 h after surgery Increased lung diffusion of tumour cells in the absence of surgery. Slightly decreased tumour load (non-statistically significant) in the presence of surgery. Franchi et al. (2007)
Syngeneic colon adenocarcinoma Immuno-competent rats Injection of tumour cells in ileocecal vein Yes (laparotomy) 20 mg·kg−1 morphine s.c. 1 day before and 2 days after tumour inoculation Reduced tumour burden Yeager and Colacchio (1991)
Syngeneic Immuno-competent rats Tail vein injection of tumour cells Yes (laparotomy) 5 mg·kg−1 i.p. 30 min before surgery, 5 mg·kg−1 s.c. in slow-release suspension immediately after surgery 5–10 mg·kg−1 s.c. in slow-release suspension 5 h after surgery Reduced tumour burden in the presence of surgical stress. No effect in the absence of surgical stress. Page et al. (1993)
Syngeneic Immuno-competent rats Tail vein injection of tumour cells Yes (laparotomy) 10 mg·kg−1 i.p. 30 min before surgery and 5 mg·kg−1 s.c. in slow-release suspension after surgery Reduced tumour burden in the presence of surgical stress, No effect in the absence of surgical stress. Page et al. (1994)
Syngeneic Immuno-competent rats Tail vein injection of tumour cells Yes (laparotomy) 8 mg·kg−1 i.p. 30 min before surgery and/or 4 mg·kg−1 s.c. immediately after surgery in a slow-release suspension and/or 2 mg·kg−1 s.c. in a slow-release suspension 5 h after surgery Reduced lung tumour burden in the presence of surgery in all treatment groups Page et al. (1998)
Syngeneic Immuno-competent rats Tail vein injection of tumour cells Yes (laparotomy) 10 mg·kg−1 i.p. at induction of anaesthesia Reduced lung retention of tumour cells in the presence of surgical stress, but no statistical significance Bar-Yosef et al. (2001)
Syngeneic Immuno-competent mice i.v. injection of tumour cells no 10 mg·kg−1 i.p. for 6 days Decreased lung metastases Harimaya et al. (2002)
Syngeneic Immuno-competent mice Ectopic (melanoma cells s.c. in hind paw) even though the authors claim orthotopic Yes (tumour-induced hyperalgesia) 5 and 10 mg·kg−1 s.c. daily for 6 days (days 16–21 post-inoculation) Analgesia was demonstrated Reduced tumour growth and metastasis Sasamura et al. (2002)
Allogeneic Immuno-compromised mice Ectopic (tumour cells inoculated s.c. in dorsal flank) No 10, 20 and 30 mg·kg−1·day−1 i.p. during first, second and third weeks after inoculation respectively Morphine concentrations checked in plasma after injection, 50–60 μM at 10–25 min, 0.9–3.4 μM at 1–2 h Decreased tumour volume for breast cancer cell lines MCF7 and MDA-MB231, no effect for colon cancer HT-29 Tegeder et al. (2003)
Allogeneic Immuno-compromised (nude) mice Ectopic (LLC implanted in the right flank s.c.) Not intentionally (but surgical insertion of the pellets) Day of tumour inoculation: 75 mg morphine pellets implanted days 7–14 20 mg·kg−1·day−1 i.p. Days 15–21, 30 mg·kg−1·day−1 i.p. Decreased tumour volume and wet weight Koodie et al. (2010)
Syngeneic Immuno-competent mice Tail vein injection of tumour cells No 10 mg·kg−1 i.p. every day for 3 days Decreased number of tumour nodules Afsharimani et al. (2014)
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Table rows highlighted in blue denote a protective effect of morphine, in red a tumour-promoting effect of morphine.

Most studies evaluating the impact of morphine on metastatic disease have not used orthotopic tumour models. Most of them utilize s.c. tumour cell inoculation or tail vein injection assays. Tail vein injections of tumour cells have been used in rats (Yeager and Colacchio, 1991; Page et al., 1993; 1994; 1998; Colacchio et al., 1994; Bar-Yosef et al., 2001; Franchi et al., 2007) and mice (Harimaya et al., 2002; Afsharimani et al., 2014) with measurement of the tumour burden in the lungs or liver. These models attempt to mimic homing and outgrowth of circulating tumour cells or cells released during surgery, at distant sites. However, cultured, usually adherent, tumour cells are likely to be different from the circulating cells that are found in increased numbers in patients undergoing surgery, as well as spontaneous circulating tumour cells (Thompson and Haviv, 2011). Furthermore, these models fail to reproduce the biology of de novo metastatic disease (Fantozzi and Christofori, 2006; Jonkers and Derksen, 2007; Valastyan and Weinberg, 2011). These defects are further complicated by the fact that most inoculated tumour cells are likely to undergo apoptosis. The massive release of tumour-related antigens may induce acute adaptive anti-tumour immune responses, which are normally absent due to the formation of immuno-suppressive networks driving escape from immune surveillance in spontaneously arising tumours (Willimsky et al., 2008). Consequently, the efficacy of immune surveillance may be overestimated in cancer cell line-based tumour models.

Orthotopic models (Gupta et al., 2002) appear appropriate if the objective of the study is to assess the effect of morphine on the growth of a primary tumour. Moreover, spontaneously metastasizing models have been proposed to present the advantage of allowing the study of the effect of morphine on metastasis. A major factor that needs to be taken into consideration is whether the animals are immuno-competent. Immunocompromised mice must be used when allogeneic tumour cells are implanted (Gupta et al., 2002; Tegeder et al., 2003; Roy et al., 2006), and, while this allows the study of cancer cells of human origin, the effects of opioids on the immune response are underestimated in such models. This is of paramount importance, as accumulating evidence indicates that the immune system plays a crucial role both at the level of the primary tumour and at distant, metastatic sites (de Visser et al., 2006; Joyce and Pollard, 2009).

The presence of pain and surgical stress in the model

In addition to perioperative pain, surgery involves an inflammatory and neuroendocrine response to tissue injury that alters immune competence including (but not limited to) the activity of natural killer cells, which play a crucial role in the metastatic process (Talmadge et al., 1980). The inclusion of pain or surgical stress into an animal model of tumour cell dissemination and growth is thus a major factor that will influence the role of opioids and the experimental outcome. Indeed, with few exceptions (Colacchio et al., 1994; Farooqui et al., 2007), morphine affords protection towards tumour growth or dissemination in the context of pain and surgical stress – elicited intentionally by laparotomy or tumour-induced hyperalgesia, or unintentionally, for example, by surgical insertion of drug-releasing pellets – but not in the absence of pain (Simon and Arbo, 1986; Yeager and Colacchio, 1991; Page et al., 1993; 1994; 1998; Bar-Yosef et al., 2001; Sasamura et al., 2002; Franchi et al., 2007). A model with no pain can specifically reveal the non-analgesic effects of morphine. In contrast, an animal tumour model, which includes pain or stress response to surgery, is better suited to represent the perioperative period in humans but does not allow dissection of the mechanisms (analgesia-mediated or -independent) of morphine's actions.

Designing new animal models to evaluate the effect of morphine on tumour growth and metastasis

Given these considerations, how should models be designed to study the effects of morphine on tumour growth and metastasis? To address this question, pre-clinical tumour models that most closely mimic the clinical setting must be carefully designed. To study the effect of morphine on metastasis independent of the surgery, one approach may be to evaluate the effects of morphine on genetically engineered mouse models of de novo tumourigenesis, which have been used successfully to study many aspects of tumour biology (Frese and Tuveson, 2007). These models are generated by tissue-specific manipulation of genes known to be relevant in a certain subtype of human cancer and allow the study of spontaneously arising tumours that closely mimic their human counterparts in an orthotopic, immuno-competent setting. However, with some exceptions (Muller et al., 1988; Boggio et al., 1998; Paez-Ribes et al., 2009), employing genetically engineered mouse models to study metastatic disease is complicated by asynchroneously arising, rapidly growing, primary tumours that do not allow sufficient time for the establishment of (advanced) metastatic disease (Francia et al., 2011). As a consequence, these models generally show a relatively low incidence of metastatic disease and do not allow the effects of morphine on advanced metastatic disease to be analysed. Another condition is required to better mimic the perioperative setting, which is that the animal model should include a surgical intervention, either primary tumour resection or a more artificial event, inducing surgical stress, tissue damage and pain.

To circumvent these limitations, and to provide information relevant to the context of cancer surgery patients, we have recently developed a pre-clinical mouse model of de novo breast cancer metastasis formation (Doornebal et al., 2013). In this model, small tumour fragments of a de novo mouse mammary tumour (Derksen et al., 2006) are orthotopically transplanted into wild-type recipients. Once mammary tumours are established, a mastectomy is performed and the mammary tumour is surgically resected. Following surgery, these mice spontaneously develop clinically overt metastatic disease in lungs, liver, spleen and lymph nodes. Using a similar approach to exploit other genetically engineered mouse models provides a unique opportunity to create models that not only reproduce the biology of de novo metastatic disease but also allows the evaluation of the effects of morphine using clinically defined outcomes – that is, metastasis-specific survival – in a context that closely mimics the perioperative setting.

The dose and mode of administration of morphine used

A wide range of morphine doses have been used in the pre-clinical experiments testing its effect on tumour growth and metastasis (Table 1), which may contribute to the differences in outcome of these studies. It has been proposed that low, sub-analgesic doses of morphine have mitogenic and angiogenic properties (Tegeder and Geisslinger, 2004). Most studies employ doses of morphine of 5–20 mg·kg−1 daily (Table 1) and very few (Tegeder et al., 2003) verify the resulting circulating morphine concentrations. Affinities of the μ-opioid receptors are not critically different between humans and mice (Ki database at http://pdsp.med.unc.edu/). However, as previously noted (Parat, 2013), rodents metabolize morphine differently from humans and produce mostly morphine-3-glucuronide (M3G) (Kuo et al., 1991), which is not analgesic (Shimomura et al., 1971). In contrast, humans produce not only M3G but also morphine-6-glucuronide (M6G), which is a more potent analgesic than morphine (Shimomura et al., 1971; Osborne et al., 1988; 1990). To achieve analgesia, doses of morphine (in mg·kg−1) are therefore much higher in mice than humans. The effect of morphine per se can only be compared between rodents and humans, if the circulating (and presumably tissue) concentrations of morphine are similar. Furthermore, given that pain influences tumour growth and metastasis (Page et al., 2001), it is important to note whether the dose of morphine employed in rodent models is actually producing analgesia, especially if the model includes pain. In addition, the metabolite M3G, predominantly produced in rodents, might have non-opioid receptor-mediated activities (see below).

Lastly, the continuity of delivery (i.e. osmotic pumps or morphine-releasing pellets vs. injections at time intervals) and the duration of morphine treatment both differ between studies. This may be important if the effect of morphine on tumours is mediated by mechanisms subject to tolerance and withdrawal, such as the immune function (West et al., 1998; Eisenstein et al., 2006). Indeed, in contrast to continuous administration by constant infusion or slow-release pellets, intermittent administration of morphine (every 12 h for 4 days) to rats was characterized as a chronic stressor, inducing withdrawal-like conditions in each interval and increasing the hypothalamic–pituitary–adrenal (HPA) axis response to novel stimuli (Houshyar et al., 2003; 2004). Activation of the HPA axis is known to facilitate cancer progression and metastasis (Li et al., 2013), via many mechanisms, including suppression of cell-mediated immunity (Benish et al., 2008), promotion of angiogenesis (Yang et al., 2009) and direct action on cancer cells (Bernabe et al., 2011). Only a few studies have tested the effect of continuous administration of morphine on tumour growth and metastasis. Koodie et al. used morphine-releasing pellets, and the studies by Page et al. mention s.c. injection of morphine in a slow-release suspension. They all resulted in anti-tumour, rather than pro-tumour effects (Page et al., 1993; 1994; 1998; Koodie et al., 2010). Implantation of a 75 mg morphine-releasing pellet in mice provided serum morphine concentrations of 7 μM at 6–24 h and 2 μM at equilibrium (Bryant et al., 1988). Patient-controlled analgesia with morphine, often used in post-operative pain management, was suggested, using pharmacokinetic simulation, to result in relatively stable effect-site concentrations of morphine and its metabolites M3G and M6G in patients (Sam et al., 2011), and animal models should therefore mimic this continuity. Of the animal studies on tumour growth and metastasis that employed doses of morphine escalating over the course of the treatment to account for the development of tolerance (Gupta et al., 2002; Tegeder et al., 2003; Farooqui et al., 2007; Koodie et al., 2010), only those using high doses (Tegeder et al., 2003; Koodie et al., 2010) demonstrated anti-tumour effects of morphine. Taken together, these observations indicate that continuous administration of high doses of morphine that produce analgesia is more likely to result in prevention of tumour growth and metastasis, in rodent models.

The receptors involved

We have limited inclusion in Table 1 to studies measuring tumour growth and metastasis in animals treated with morphine, but it should be noted that further studies using genetic or pharmacological manipulation of the μ-opioid receptor (nomenclature follows Alexander et al., 2013) have been carried out. Overexpression and down-regulation of the μ-opioid receptor in cancer cells before injecting them into mice were shown to increase and decrease, respectively, primary tumour growth and metastasis in mice expressing μ-opioid receptors (Biji et al., 2011; Lennon et al., 2012). In addition, infusion of the μ-opioid receptor antagonist methylnaltrexone reduced tumour growth and metastasis in wild-type mice (Biji et al., 2011). Growth of cancer cells expressing μ-opioid receptors in mice lacking μ-opioid receptors (knockout mice) was also reduced compared with that in wild-type mice. This indicates that μ-opioid receptor activation on both tumour cells and cells of the host may promote tumour growth and metastasis. However, neither of these studies have included evidence that morphine increases tumour growth and metastasis in vivo (Biji et al., 2011; Lennon et al., 2012).

Very little is known about the possible consequences of μ-opioid receptor dimerization on cancer. A role for μ- and δ-opioid receptor heterodimerization has been suggested in natural killer cells, in terms of their cytolytic function, with reciprocal regulation of each receptor homodimerization and potential consequences on tumour growth (Sarkar et al., 2012). In addition, activation of opioid receptors other than μ-receptors may contribute to the role of morphine in cancer, depending upon the doses of morphine involved. Expression of μ-, δ- and κ-opioid receptors has been detected in cancer cell lines and in tumour tissue (Nylund et al., 2008; Tang et al., 2013; Zhang et al., 2013; Zylla et al., 2013), and some studies suggest that opioid receptors in tumours are up-regulated, compared with control tissue (Madar et al., 2007; Biji et al., 2011; Tang et al., 2013; Zhang et al., 2013). In situ detection of opioid receptor expression in tumour stroma is lacking, although endothelial, immune and fibroblast cells are known to express opioid receptors in non-tumour contexts (Stefano et al., 1995; Sharp, 2006; Cheng et al., 2008). Similarly, endogenous opioids can be produced by cancer cells and are detected in some tumours (Bostwick et al., 1987; Krajnik et al., 2010) where they modulate cancer progression (Boehncke et al., 2011) presumably via regulation of tumour-associated immune cells (Ohmori et al., 2009; Boehncke et al., 2011). Lastly, whether μ-opioid receptor alternative splicing, which results in multiple variants in both humans and mice, modulates tumour growth is underexplored.

A growing amount of studies looking for non-GPCR-mediated actions of opioids on immune pathways have identified that the Toll-like receptor 4 (TLR4), which is activated by LPS produced by bacteria, may respond to opioids. One group has proposed that opioid receptor ligands produce a slight but significant activation (morphine) or antagonism (naloxone) of the TLR4, in a non-stereospecific fashion, i.e. the (+) enantiomers were active at TLR4 receptors but not at opioid receptors (Wang et al., 2012). In contrast, others have suggested that morphine produced, by itself, a slight activation of TLR4, but inhibited TLR4 activation by LPS in a non-competitive fashion, as did naloxone (Stevens et al., 2013). Interestingly, M3G, which has limited opioid receptor activity (Ulens et al., 2001), induced activation of TLR4 (Lewis et al., 2010; Due et al., 2012). This might be of considerable importance if TLR4 mediates some of the effects of opioids on cancer growth and metastasis, as rodent models employ high doses of morphine that result in high doses of M3G in the circulation (Zelcer et al., 2005) and, presumably, at tissue level.

Lastly, a variety of mouse strains are used in experiments testing the effect of morphine on tumour growth and metastasis, and they may respond differently to the drug since it is known that different mouse strains exhibit polymorphisms in the 5′ flanking region and 3′ untranslated region of the μ-opioid receptor gene that are associated with differences in opioid sensitivity (measured as locomotor hyperactivity and antinociception) (Shigeta et al., 2008). The immunosuppressive effects of morphine are also likely to vary between mouse strains. This was clearly shown for the direct effect of morphine on mouse spleen cells (Eisenstein et al., 1995).

The cells targeted by morphine

A major question remains whether the putative effects of morphine on tumour growth and metastasis might be mediated by direct activation of cellular receptors or indirectly mediated by morphine-initiated effects that lead to the release of secondary factors. The cells on which morphine can act directly to modulate the growth and metastasis of tumours include the cancer cells as well as other cell types such as immune cells, and cells of the tumour microenvironment such as tumour-associated macrophages and endothelial cells. Experiments employing disruption of the μ-opioid receptor show that opioid receptor activation on the cancer cells injected into the mice as well as the cells of the tumour-bearing animal can interfere with tumour growth and metastasis (Biji et al., 2011; Lennon et al., 2012).

Much of the literature on the effect of morphine on the immune response has assessed the functions of immune cells collected from mice or humans after they were given morphine, thereby testing potential indirect and direct effects of morphine on those cells. However, morphine added to immune cells ex vivo also showed some direct effects (Eisenstein et al., 1995; Condevaux et al., 2001; Malik et al., 2002; Fuggetta et al., 2005). Macrophage phagocytic ability was inhibited by acute, but not chronic, direct exposure to morphine in vitro (Casellas et al., 1991; Tomei and Renaud, 1997). This phenomenon occurred via activation of opioid receptors (Tomassini et al., 2003) and was subject to ‘in vitro withdrawal’ (Tomei and Renaud, 1997). In co-cultures of tumour cells with macrophages, morphine prevented paracrine communication through which macrophages could promote the production of matrix-degrading enzymes by the tumour cells (Afsharimani et al., 2014). A direct effect of morphine on endothelial cells has also been proposed (Gupta et al., 2002; Singleton et al., 2006; Leo et al., 2009) and suggests pro-angiogenic properties for low concentrations of morphine. All these reports suggest that some of the effects of morphine in vivo might be mediated by direct action on the immune or endothelial cells.

In line with in vivo data showing that the dose and mode of administration influenced the effect of morphine on tumours, at the cellular level, responses that may be involved in tumour progression, such as proliferation or apoptosis, or immune cell responses, have also been shown to depend upon the concentration of morphine applied, with low doses promoting cell proliferation and high doses promoting apoptosis, and to be susceptible to development of tolerance and receptor desensitization (see Tegeder and Geisslinger, 2004; Eisenstein et al., 2006).

Conclusion and perspectives

To extrapolate animal experimental data to human patients, mouse models used to study the effects of morphine on tumour growth and metastasis should adhere to the following criteria. The mice should spontaneously develop orthotopic primary tumours in an immuno-competent setting. In addition, the tumour models should reproduce the biology of de novo metastatic disease. To relate the animal data to perioperative use of morphine in cancer surgery patients, surgical resection of the primary tumour is desirable as part of the model. The doses of morphine used should be analgesic in mice and the duration of morphine exposure should match post-operative analgesia regimens, avoiding unnecessary withdrawal as much as possible.

Overall, the current literature does not provide definitive evidence for a modulation of tumour growth and metastasis by morphine. Morphine might modulate tumour growth and metastasis though a combination of direct (on cells) and indirect (neuroendocrine) responses, central and peripheral mechanisms and modulation of physiopathological functions key to tumour development, such as inflammation, stress and pain. It is further likely that the effects of morphine are in addition to the effects of endogenous opioids and are regulated by tolerance and withdrawal responses. The discrepancies found in the literature are thus not surprising, and refining the animal models that we use, on the basis of all these criteria, will hopefully provide, in the future, definitive answers than can be taken into consideration for patient care.

Acknowledgments

M.-O. P. and P. J. C acknowledge the financial support of the Australian and New Zealand College of Anaesthetists.

Glossary

Abbreviations

HPA

hypothalamic–pituitary–adrenal

M3G

morphine-3-glucuronide

M6G

morphine-6-glucuronide

TLR

Toll-like receptors

Conflict of interest

The authors declare no conflict of interest.

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