Targeting putative mu opioid/metabotropic glutamate receptor-5 heteromers produces potent antinociception in a chronic murine bone cancer model

Smeester, Branden A.; Lunzer, Mary M.; Akgün, Eyup; Beitz, Alvin J.; Portoghese, Philip S.

doi:10.1016/j.ejphar.2014.09.008

Cited by 41 publications

(45 citation statements)

References 25 publications

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“…Implantation into the calcaneus bone of the hind paw was performed as previously described (Wacnik et al, 2001, Smeester et al, 2014). Briefly, mice were placed in an enclosed plexi-glas chamber and initially anesthetized with 3% isoflurane/3 L oxygen.…”

Section: Methodsmentioning

confidence: 99%

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Colocalization of aromatase in spinal cord astrocytes: Differences in expression and relationship to mechanical and thermal hyperalgesia in murine models of a painful and a non-painful bone tumor

et al. 2015

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While spinal cord astrocytes play a key role in the generation of cancer pain, there have been no studies that have examined the relationship of tumor-induced astrocyte activation and aromatase expression during the development of cancer pain. Here, we examined tumor-induced mechanical hyperalgesia and cold allodynia, and changes in GFAP and aromatase expression in murine models of painful and non-painful bone cancer. We demonstrate that implantation of fibrosarcoma cells, but not melanoma cells, produces robust mechanical hyperalgesia and cold allodynia in tumor-bearing mice compared to saline-injected controls. Secondly, this increase in mechanical hyperalgesia and cold allodynia is mirrored by significant increases in both spinal astrocyte activity and aromatase expression in the dorsal horn of fibrosarcoma-bearing mice. Importantly, we show that aromatase is only found within a subset of astrocytes and not in neurons in the lumbar spinal cord. Finally, administration of an aromatase inhibitor reduced tumor-induced hyperalgesia in fibrosarcoma-bearing animals. We conclude that a painful fibrosarcoma tumor induces a significant increase in spinal astrocyte activation and aromatase expression and that the up-regulation of aromatase plays a role in the development of bone tumor-induced hyperalgesia. Since spinal aromatase is also upregulated, but to a lesser extent, in non-painful melanoma bone tumors, it may also be neuroprotective and responsive to the changing tumor environment.

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Section: Methodsmentioning

confidence: 99%

“…Tumor-induced mechanical hyperalgesia was tested using von Frey filaments (#3.61- C3H mice and #1.65 - B6C3) (Smeester et al, 2012, Smeester et al, 2013, Smeester et al, 2014). These filaments produce forces of 400 mg and 8 mg respectively.…”

Section: Methodsmentioning

confidence: 99%

Colocalization of aromatase in spinal cord astrocytes: Differences in expression and relationship to mechanical and thermal hyperalgesia in murine models of a painful and a non-painful bone tumor

et al. 2015

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“…MMG22 was found to produce profound antinociception without tolerance in mouse models of inflammatory pain [2] and bone cancer-induced pain [53]. Here we present data that MMG22 is antiallodynic in nerve injury-induced neuropathic pain, although likely through the targeting of single MOR and mGluR5 receptors rather than MOR-mGluR5 heteromers.…”

Section: Introductionmentioning

confidence: 71%

“…It has been previously shown that the number of atoms that comprise the spacer length between the two pharmacophores can greatly impact the potency of bivalent ligands [16], including those with the oxymorphone and MPEP pharmacophores [53]. Therefore, we conducted a direct side-by-side comparison of dose-effect of MMG22 (spacer length of 22 atoms) and MMG10 (spacer length of 10 atoms).…”

Section: Resultsmentioning

confidence: 99%

Bivalent ligand that activates mu opioid receptor and antagonizes mGluR5 receptor reduces neuropathic pain in mice

Peterson

Kitto

Akgün

et al. 2017

Pain

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The mu opioid receptor (MOR) and metabotropic glutamate receptor 5 (mGluR5) are well-established pharmacological targets in the management of chronic pain. Both receptors are expressed in spinal cord. MMG22, a bivalent ligand containing two pharmacophores separated by 22 atoms that simultaneously activates MOR and antagonizes mGluR5 has been shown to produce potent reversal of tactile hypersensitivity in rodent models of LPS- and bone-cancer-induced chronic pain. The present study assessed whether intrathecal MMG22 also is effective in reducing pain of neuropathic origin. Further, we theorized that MMG22 should reduce hyperalgesia in nerve-injured mice in a manner consistent with a synergistic interaction between MOR and mGluR5. Several weeks following spared nerve injury, tactile hypersensitivity was reversed in mice by intrathecal injection of MMG22 (0.01–10 nmol) but also by its shorter spacer analog, MMG10, with similar potency. The potencies of the bivalent ligands were 10-14-fold higher than those of the compounds upon which the bivalent structure was based, the MOR agonist oxymorphone and the mGluR5 antagonist MPEP. Co-administration of oxymorphone and MPEP demonstrated analgesic synergism, an interaction confirmed by isobolographic analysis. The present study indicates that in the spared nerve-injury induced model of neuropathic pain, the two pharmacophores of the bivalent ligands MMG22 and MMG10 target MOR and mGluR5 as separate receptor monomers. The observed increase in potency of MMG22 and MMG10, compared to oxymorphone and MPEP, may reflect the synergistic interaction of the two pharmacophores of the bivalent ligand acting at their respective separate receptor monomers.

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“…Osteosarcoma is the most common malignant bone tumor found in children and adolescents and is associated with many complications including metastases and intractable cancer pain [1,2]. Typically, the prevalence of osteosarcoma shows a strong relationship with skeletal growth.…”

Section: Introductionmentioning

confidence: 99%

Osteosarcomagenesis: Biology, Development, Metastasis, and Mechanisms of Pain

Smeester¹,

Moriarity²,

Beitz³

2017

Osteosarcoma - Biology, Behavior and Mechanisms

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Osteosarcoma is the most common primary cancer of the bone and third most common cancer in children and adolescents with approximately 900 new cases annually in the United States. A major facet of osteosarcoma is its high level of genomic instability, in particular chromosomal instability, which is the result of increased or decreased chromosome number in a cell. Furthermore, pain is the most common symptomatic feature of osteosarcoma that lacks efective therapy. Pain in osteosarcoma is relatively more complicated than many other painful conditions requiring a more thorough understanding of its etiology, pathobiology, and neurobiology to allow the development of beter therapies for reducing pain in osteosarcoma patients. Studies are underway to deine the diverse modalities of presentation, growth, development, metastases, and nociception in osteosarcoma. New data from human studies in combination with data from studies incorporating transgenic mouse models of osteosarcoma are providing valuable insights into the mechanisms underlying the development of both the tumor and the tumor-induced pain. These new data will undoubtedly lead to improved prognoses, as well as the development of novel therapeutics that will signiicantly decrease bone cancer pain.

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Targeting putative mu opioid/metabotropic glutamate receptor-5 heteromers produces potent antinociception in a chronic murine bone cancer model

Cited by 41 publications

References 25 publications

Colocalization of aromatase in spinal cord astrocytes: Differences in expression and relationship to mechanical and thermal hyperalgesia in murine models of a painful and a non-painful bone tumor

Colocalization of aromatase in spinal cord astrocytes: Differences in expression and relationship to mechanical and thermal hyperalgesia in murine models of a painful and a non-painful bone tumor

Bivalent ligand that activates mu opioid receptor and antagonizes mGluR5 receptor reduces neuropathic pain in mice

Osteosarcomagenesis: Biology, Development, Metastasis, and Mechanisms of Pain

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