Targeting MOR-mGluR5 heteromers reduces bone cancer pain by activating MOR and inhibiting mGluR5
Introduction
Pain is among the most common symptoms in cancer patients and is estimated to affect 90% of patients with end-stage cancer (Marcus, 2011). Of the millions of patients diagnosed with cancer, approximately 58% suffer from intolerable pain, which increases to 85% of the population as the disease becomes terminal (Marcus, 2011).
Pain is usually associated with emotional distress and decreased function, and negatively affects the patient's quality of life (Abram, 1989, Marcus, 2011). Although opioids are the primary class of analgesics used to treat severe cancer pain, these drugs have adverse side effects that include nausea, sedation, constipation, tolerance, dependence, respiratory depression and overdose-related death that limit their use (Mantyh, 2006). Therefore, there is an urgent need to develop new and effective treatments for cancer pain that lack the serious side effects associated with opioids.
Earlier studies showed that co-administration of a mu opioid receptor (MOR) agonist and metabotropic glutamate receptor 5 (mGluR5) antagonist reduced morphine analgesic tolerance and dependence, and augmented its antinociceptive properties (Kozela et al., 2003, Sotgiu et al., 2003). The interaction between MOR and mGluR5, their expression in astrocytes and neurons, and evidence that MOR/mGluR5 heteromers exist in cultured cells (Brasseur, 1997, Schröder et al., 2009), led to the development of MMG22. MMG22 is a bivalent ligand consisting of an oxymorphone-derived MOR agonist and the mGluR5 antagonist, M-MPEP, tethered by a 22-atom spacer (Akgün et al., 2013). Significantly, intrathecal (i.t.) administration of MMG22 exhibited thousands of fold greater potency based on ED50 in murine models of LPS-induced inflammatory pain relative to naïve mice. The necessity of inflammation as a condition for efficacy also was observed in a murine model of cancer pain in which osteolytic fibrosarcoma cells were implanted into and around the calcaneus bone (Smeester et al., 2014).
Intrathecal administration of MMG22 afforded antinociception that was three orders of magnitude more effective than morphine, a gold standard for reducing tumor-evoked hyperalgesia (Wacnik et al., 2001). That MMG22 exhibited 38,000-times greater potency than a mixture of the individual monovalent ligands containing MOR agonist and mGluR5 antagonist pharmacophores supports the notion that MMG22 interacts with a MOR-mGluR5 heteromer (Akgün et al., 2013). The exceptional potency of MMG22 may be a result of optimal bridging of the two protomers of the putative MOR-mGluR5 heteromer.
In the present study, we show that systemic administration of MMG22 is highly effective at reducing cancer pain. The extraordinary potency of MMG22 and lack of side effects typically associated with opioids, suggests that MMG22 is an attractive alternative to morphine in managing cancer pain.
Section snippets
Subjects
Adult male C3H/HeNCr MTV mice (Charles River; 25–30 g) were used. Mice were housed four per cage, allowed free access to food and water, and maintained on a 12-h light/dark schedule. All protocols and procedures were approved by the University of Minnesota Institutional Animal Care and Use Committee and were conducted according to the guidelines established by the International Association for the Study of Pain (Zimmermann, 1983).
Cancer cell implantation
NCTC clone 2472 fibrosarcoma cells (American Type Culture
MMG22 dose-dependently reduces tumor-evoked hyperalgesia
Systemic administration of MMG22 potently reduced tumor-evoked mechanical hyperalgesia as defined by MPE% derived from the formula above (Fig. 2). Subcutaneous, intramuscular, and oral administration each reduced hyperalgesia dose dependently. Depending on the dose, the antihyperalgesia peaked at 30–60 min after administration and persisted for at least 4 h. Hyperalgesia returned to baseline levels by 24 h. Interestingly, s.c. administration not only produced potent antihyperalgesia, but also
Discussion
The design of the bivalent ligand MMG22 was based on studies showing that opioid receptors can form heteromers with multiple types and classes of GPCRs (Costantino et al., 2012), and on evidence indicating that MOR and mGluR5 interact functionally (Schröder et al., 2009). Receptor dimerization can alter receptor function, ligand pharmacology, signal transduction, and cellular trafficking (Hiller et al., 2013). Importantly, the formation of heteromers may be modulated in pathological states (
Funding sources
This work was supported by NIH grants HL135895 (DAS), DA030316 (PSP), and 2T32 DA007234-31 (SJE and RS).
Conflicts of interest
The authors have no conflicts of interest to disclose.
Acknowledgements
This work was supported by NIH grants HL135895 (DAS), DA030316 (PSP), and 2T32 DA007234-31 (SJE and RS). We thank Mr. Malcolm Johns for assistance in culturing the cancer cells and Dr. Iryna Khasabova for statistical advice.
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