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

Zhou, Quanhong; Wang, Jing; Zhang, Xin; Zeng, Lulu; Wang, Li; Jiang, Wei

doi:10.1016/j.ejphar.2013.09.009

Cited by 20 publications

(18 citation statements)

References 22 publications

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“…In particular, mGlu4 and mGlu5 are relevant targets for allosteric modulation because they functionally oppose each other, where mGlu4 negatively regulates adenylyl cyclase and mGlu5 positively regulates phospholipase C 13 . This means mGlu5 inhibition or mGlu4 stimulation can potentially treat anxiety 14–16 , chronic pain 17–21 and Parkinson’s disease 22, 23 . Indeed, one of the most well characterized allosteric modulators that binds both receptors, 2-Methyl-6-(phenylethynyl)pyridine (MPEP), is a negative allosteric modulator (NAM) and inverse agonist of mGlu5 as well as a positive allosteric modulator (PAM) of mGlu4, giving it dual functional behaviour 24 .…”

Section: Introductionmentioning

confidence: 99%

Analysis of positive and negative allosteric modulation in metabotropic glutamate receptors 4 and 5 with a dual ligand

Dalton

Giraldo

2017

Sci Rep

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As class C GPCRs and regulators of synaptic activity, human metabotropic glutamate receptors (mGluRs) 4 and 5 are prime targets for allosteric modulation, with mGlu5 inhibition or mGlu4 stimulation potentially treating conditions like chronic pain and Parkinson’s disease. As an allosteric modulator that can bind both receptors, 2-Methyl-6-(phenylethynyl)pyridine (MPEP) is able to negatively modulate mGlu5 or positively modulate mGlu4. At a structural level, how it elicits these responses and how mGluRs undergo activation is unclear. Here, we employ homology modelling and 30 µs of atomistic molecular dynamics (MD) simulations to probe allosteric conformational change in mGlu4 and mGlu5, with and without docked MPEP. Our results identify several structural differences between mGlu4 and mGlu5, as well as key differences responsible for MPEP-mediated positive and negative allosteric modulation, respectively. A novel mechanism of mGlu4 activation is revealed, which may apply to all mGluRs in general. This involves conformational changes in TM3, TM4 and TM5, separation of intracellular loop 2 (ICL2) from ICL1/ICL3, and destabilization of the ionic-lock. On the other hand, mGlu5 experiences little disturbance when MPEP binds, maintaining its inactive state with reduced conformational fluctuation. In addition, when MPEP is absent, a lipid molecule can enter the mGlu5 allosteric pocket.

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Section: Introductionmentioning

confidence: 99%

Analysis of positive and negative allosteric modulation in metabotropic glutamate receptors 4 and 5 with a dual ligand

Dalton

Giraldo

2017

Sci Rep

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“…Specifically, LSP4-2022 [(2S)-2-amino-4-({[4-(carboxymethoxy) phenyl](hydroxy)methyl}(hydroxy)phosphoryl)butanoic acid], a novel mGluR4 agonist, dose-dependently inhibited mechanical allodynia caused by carrageenan inflammation, with complementary results produced with mGluR4 antisense oligodeoxynucleotides and in mGlu4 knockout mice (Vilar et al, 2013). However, opposing results were found with selective mGluR5 antagonists, with which thermal allodynia was inhibited and mechanical allodynia was enhanced in the SNL model of neuropathic pain (Zhou et al, 2013). Activation of mGluR5 within the CeA via microinjection of selective agonists was also found to induce both somatic and visceral pain-like behaviors, effects blocked with selective antagonists (Kolber et al, 2010;Crock et al, 2012).…”

Section: Receptors In Stress Pathways That Modulate Nociceptionmentioning

confidence: 75%

Stress-Induced Pain: A Target for the Development of Novel Therapeutics

Johnson

Meerveld

2014

J Pharmacol Exp Ther

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Although current therapeutics provide relief from acute pain, drugs used for treatment of chronic pain are typically less efficacious and limited by adverse side effects, including tolerance, addiction, and gastrointestinal upset. Thus, there is a significant need for novel therapies for the treatment of chronic pain. In concert with chronic pain, persistent stress facilitates pain perception and sensitizes pain pathways, leading to a feed-forward cycle promoting chronic pain disorders. Stress exacerbation of chronic pain suggests that centrally acting drugs targeting the pain-and stress-responsive brain regions represent a valid target for the development of novel therapeutics. This review provides an overview of how stress modulates spinal and central pain pathways, identifies key neurotransmitters and receptors within these pathways, and highlights their potential as novel targets for therapeutics to treat chronic pain.

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“…Subcellular expression patterns of mGluR5 appear altered under conditions of neuropathic pain; a reduction in plasma membrane and an increase in nuclear membrane expression of mGluR5 following spared nerve injury has recently been observed [62]. MPEP moderately reduces tactile [43; 67; 68] and cold [43] hypersensitivity in nerve-injured mice. Systemically or spinally delivered MPEP reduces spontaneous and evoked responses of wide dynamic range neurons in nerve-injured rodents [54].…”

Section: Discussionmentioning

confidence: 99%

“…Systemically or spinally delivered MPEP reduces spontaneous and evoked responses of wide dynamic range neurons in nerve-injured rodents [54]. MPEP also potentiates morphine inhibition of neuropathic pain [43; 67] and reduces opioid analgesic tolerance [43; 67]. There is evidence for MPEP effects on NR2B-containing NMDA receptors [37], which may explain its inhibition of the development of opioid tolerance.…”

Section: Discussionmentioning

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

Cited by 20 publications

References 22 publications

Analysis of positive and negative allosteric modulation in metabotropic glutamate receptors 4 and 5 with a dual ligand

Analysis of positive and negative allosteric modulation in metabotropic glutamate receptors 4 and 5 with a dual ligand

Stress-Induced Pain: A Target for the Development of Novel Therapeutics

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

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