Modulation of Chronic Pain by Metabotropic Glutamate Receptors

Chiechio, Santina

doi:10.1016/bs.apha.2015.11.001

Cited by 49 publications

(39 citation statements)

References 163 publications

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“…(), our results demonstrated no difference to the cytostructure to laminae I‐III despite alteration in gene expression in the absence of descending input. Of significant interest is the alteration of the metabotropic glutamate receptors, in which maladaptive mGluR expression has been linked to neuropathic pain, allodynia and hyperalgesia (Mills et al ., ; Kolber, ; Chiechio, ). Our results demonstrate that mGluR expression increased between 15 and 25% following a STx in laminae I‐III.…”

Section: Discussionmentioning

confidence: 99%

Altered transcription of glutamatergic and glycinergic receptors in spinal cord dorsal horn following spinal cord transection is minimally affected by passive exercise of the hindlimbs

Chopek

MacDonell

Shepard

et al. 2018

Eur J of Neuroscience

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Gene expression is altered following a spinal transection (STx) in both motor and sensory systems. Exercise has been shown to influence gene expression in both systems post-STx. Gene expression alterations have also been shown in the dorsal root ganglia and nociceptive laminae of the spinal cord following either an incomplete spinal cord injury (SCI) or a contusive SCI. However, the effect of STx and exercise on gene expression in spinal cord laminae I-III has not fully been examined. Therefore, the purpose of this study was to determine whether gene expression in laminae I-III is altered following STx and determine whether superimposed passive exercise of the hindlimbs would influence gene expression post-STx in laminae I-III. Laser capture microdissection was used to selectively harvest laminae I-III of lumbar spinal cord sections, and quantitative RT-PCR was used to examine relative expression of 23 selected genes in samples collected from control, STx and STx plus exercise rats. We demonstrate that post-STx, gene expression for metabotropic glutamate receptors 1, 5 and 8 were up-regulated, whereas ionotropic glutamatergic receptor (Glur2) and glycinergic subunit GLRA1 expression was down-regulated. Daily exercise attenuated the down-regulation of Glur2 gene expression in laminae I-III. Our results demonstrate that in a STx model, gene expression is altered in laminae I-III and that although passive exercise influences gene expression in both the motor and sensory systems, it had a minimal effect on gene expression in laminae I-III post-STx.

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Section: Discussionmentioning

confidence: 99%

Altered transcription of glutamatergic and glycinergic receptors in spinal cord dorsal horn following spinal cord transection is minimally affected by passive exercise of the hindlimbs

Chopek

MacDonell

Shepard

et al. 2018

Eur J of Neuroscience

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“…There is evidence for MPEP effects on NR2B-containing NMDA receptors [37], which may explain its inhibition of the development of opioid tolerance. There remains interest in developing therapeutic negative allosteric modulators that selectively target mGluR5 [14; 65]. However, higher doses of systemically delivered MPEP (100 mg/kg) and the analog MTEP (30–100 mg/kg) resulted in reduction of locomotor activity and impairment of rotarod performance[68].…”

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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“…102 Group I mGluR antagonists have an analgesic action by an effect upon peripheral terminal, spinally and at supraspinal sites. 103 Group II mGluR agonists regulate neurotransmitter release and depress pain transmission by acting at different levels of pain neuraxis, including nociceptors, dorsal horn and supraspinal regions such as the amygdala and PAG. 104 Group III mGluR agonists are also involved in the control of hyperalgesia following inflammation.…”

Section: Survey Of Current Targets Of Pain Therapeuticsmentioning

confidence: 99%

“…As with the other metabotrophic receptors, agonist injections into a peripherally inflamed site or into the spinal dorsal horn regulates glutamatergic transmission in inflammatory and neuropathic pain. 103 Group I mGluRs antagonists and Groups II and III mGluRs agonists exhibited analgesic properties in neuropathic or inflammatory pain states 105–112 and may serve as a basis to develop future spinally-targeted agents. 113,114 Importantly, antagonists affecting Group I mGluRs, have minimal impact on fast synaptic transmission and minimal cognitive effects as compared to ionotropic glutamate antagonists.…”

Section: Survey Of Current Targets Of Pain Therapeuticsmentioning

confidence: 99%

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

Knezevic

Yekkirala

Yaksh

2017

Anesthesia &Amp; Analgesia

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Opioids Opioids represent an efficacious therapeutic modality for some, but not all pain states. Singular reliance on opioid therapy for pain management, has limitations and abuse potential has deleterious consequences for patient and society. Our understanding of pain biology has yielded insights and opportunities for alternatives to conventional opioid agonists. The aim is to have efficacious therapies, with acceptable side effect profiles and minimal abuse potential, which is to say an absence of re-enforcing activity in the absence of a pain state. The present work provides a non-exclusive overview of current drug targets and potential future directions of research and development. We discuss channels activators and blockers, including: sodium channel blockers, potassium channel activators and calcium channel blockers; glutamate receptor targeted agents, including: NMDA, AMPA and metabotropic receptors). Further, we discuss therapeutics targeted at GABA, alpha2 adrenergic and opioid receptors. We also considered antagonists of angiotensin 2 and Toll receptors, and agonists/antagonists of adenosine, purine receptors. And cannabinoids. Novel targets considered are those focusing on lipid mediators and anti-inflammatory cytokines. Of interest is development of novel targeting strategies which produce long-term alterations in pain signaling, including viral transfection and toxins. We consider issues in the development of drugable molecules, including preclinical screening. While there are examples of successful translation, mechanistically promising pre-clinical candidates may unexpectedly fail during clinical trials because the preclinical models may not recapitulate the particular human pain condition being addressed. Molecular target characterization can diminish the disconnect between preclinical and humans’ targets, which should assist in developing non-addictive analgesics.

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Modulation of Chronic Pain by Metabotropic Glutamate Receptors

Cited by 49 publications

References 163 publications

Altered transcription of glutamatergic and glycinergic receptors in spinal cord dorsal horn following spinal cord transection is minimally affected by passive exercise of the hindlimbs

Altered transcription of glutamatergic and glycinergic receptors in spinal cord dorsal horn following spinal cord transection is minimally affected by passive exercise of the hindlimbs

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

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

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