Elsevier

Neuropharmacology

Volume 160, 1 December 2019, 107690
Neuropharmacology

Targeting MOR-mGluR5 heteromers reduces bone cancer pain by activating MOR and inhibiting mGluR5

https://doi.org/10.1016/j.neuropharm.2019.107690Get rights and content

Highlights

  • Systemic administration OF MMG22 targets a MOR-mGluR5 heteromer and potently reduces bone cancer pain in mice.

  • MMG22 does not possess adverse effects associated with traditional opioids.

  • MMG22 activates MOR and antagonizes mGluR5.

Abstract

Pain is among the most common symptoms in cancer and approximately 90% of patients experience end-stage cancer pain. The management of cancer pain is challenging due to the significant side effects associated with opioids, and novel therapeutic approaches are needed. MMG22 is a bivalent ligand containing MOR agonist and mGluR5 antagonist pharmacophores joined by a 22-atom spacer. MMG22 exhibited extraordinary analgesia following intrathecal administration in a mouse model of bone cancer pain. Here, we assessed the effectiveness of systemic administration of MMG22 in reducing cancer pain and evaluated whether MMG22 displays side effects associated with opioids. Fibrosarcoma cells were injected into and around the calcaneus bone in C3H mice. Mechanical hyperalgesia was defined as an increase in the paw withdrawal frequencies (PWFs) evoked by application of a von Frey monofilament (3.9 mN bending force) applied to the plantar surface of the hind paw

Subcutaneous (s.c.), intramuscular (i.m.), and oral (p.o.) administration of MMG22 produced robust dose-dependent antihyperalgesia, whose ED50 was orders of magnitude lower than morphine. Moreover, the ED50 for MMG22 decreased with disease progression. Importantly, s.c. administration of MMG22 did not produce acute (24 h) or long-term (9 days) tolerance, was not rewarding (conditioned place preference test), and did not produce naloxone-induced precipitated withdrawal or alter motor function. A possible mechanism of action of MMG22 is discussed in terms of inhibition of spinal NMDAR via antagonism of its co-receptor, mGluR5, and concomitant activation of neuronal MOR. We suggest that MMG22 may be a powerful alternative to traditional opioids for managing cancer pain.

This article is part of the Special Issue entitled ‘New Vistas in Opioid Pharmacology’.

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.

References (38)

  • Q. Zhou et al.

    Effect of metabotropic glutamate 5 receptor antagonists on morphine efficacy and tolerance in rats with neuropathic pain

    Eur. J. Pharmacol.

    (2013)
  • M. Zimmermann

    Ethical guidelines for investigations of experimental pain in conscious animals

    Pain

    (1983)
  • S.E. Abram

    Perceived dangers from intraspinal steroid injections

    Arch. Neurol.

    (1989)
  • E. Akgün et al.

    Ligands that interact with putative MOR-mGluR5 heteromer in mice with inflammatory pain produce potent antinociception

    Proc. Natl. Acad. Sci. Unit. States Am.

    (2013)
  • E. Akgün et al.

    Combined glia inhibition and opioid receptor agonism afford highly potent analgesics without tolerance

    ACS Chem. Neurosci.

    (2019)
  • G. Bhave et al.

    Peripheral group I metabotropic glutamate receptors modulate nociception in mice

    Nat. Neurosci.

    (2001)
  • L. Brasseur

    [Review of current pharmacologic treatment of pain]

    Drugs

    (1997)
  • R.M. Brown et al.

    mGlu5 receptor functional interactions and addiction

    Front. Pharmacol.

    (2012)
  • C.M. Costantino et al.

    Opioid receptor heteromers in analgesia

    Expert Rev. Mol. Med.

    (2012)
  • Cited by (13)

    • Endogenous opiates and behavior: 2019

      2021, Peptides
      Citation Excerpt :

      The CB2 agonist AM1710 differentially suppressed distinct pathological pain states and attenuated morphine tolerance and withdrawal [490]. CB1 and DOR heteromers alleviated chemotherapy-induced neuropathic pain [806]. Tramadol and the CB1 agonist, CP55940 produced dose-dependent depression of ICSS, whereas morphine enhanced CP55940-induced antinociception [23].

    • Chemical biology of noncanonical G protein–coupled receptor signaling: Toward advanced therapeutics

      2020, Current Opinion in Chemical Biology
      Citation Excerpt :

      Olson et al. [31] designed a first-in-class bivalent antagonist with an optimized spacer length for the δ-opioid receptor (DOR) and μ-opioid receptor (MOR) heterodimer (DOR–MOR), which was used to define a previously uncharacterized physiological role of DOR–MOR in promotion of chronic opioid dependence. Rational structure-based design of bivalent agonist–antagonist drugs for the C–C chemokine receptor type 5 (CCR5)-MOR and metabotropic glutamate receptor 5 (mGluR5)-MOR heteromers led to the development of MCC22 [33] and MMG22 ligands [34] (Figure 2b), respectively, which demonstrated unprecedented potency and were highly effective in reducing cancer pain [34] and inflammation-related chronic pain without tolerance in rodent models [33]. Interestingly, MMG22 was postulated to induce de novo heteromer formation by bridging mGluR5 and MOR and was only potent in inflamed animals, suggesting that dimerization occurs specifically under inflammatory conditions [35].

    View all citing articles on Scopus
    View full text