The therapeutic management of chronic
pain associated with many
cancers is problematic due to the development of tolerance and other adverse effects during the
disease progression. Recently we reported on a bivalent
ligand (MMG22) containing both mu agonist and mGluR5 antagonist pharmacophores that produced potent antinociception in mice with LPS-induced acute inflammatory
pain via a putative MOR-mGluR5 heteromer. In the present study we have investigated the antinociception of MMG22 in a mouse model of
bone cancer pain to determine its effectiveness in reducing this type of chronic nociception. There was a 572-fold increase in the potency of MMG22 over a period of 3-21 days that correlated with the progressive increase in
hyperalgesia induced by bone
tumor growth following implantation of
fibrosarcoma cells in mice. The enhancement of antinociception with the progression of the
cancer is possibly due to inhibition of
NMDA receptor-mediated
hyperalgesia via antagonism of mGluR5 and concomitant activation of MOR by the MMG22-occupied heteromer. Notably, MMG22 was 3.6-million-fold more potent than
morphine at PID 21. Since MMG22 exhibited a 250,000-times greater potency than that of a mixture of the mu
opioid (M19) agonist and mGluR5 antagonist (MG20) monovalent
ligands, the data suggest that targeting the putative MOR-mGluR5 heteromer is far superior to univalent interaction with receptors in reducing
tumor-induced nociception. In view of the high potency, long duration (>24h) of action and minimal side effects, MMG22 has the potential to be a superior pharmacological agent than
morphine and other
opiates in the treatment of chronic
cancer pain and to serve as a novel pharmacologic tool.