mGlu5 receptors and nociceptive function II. mGlu5 receptors functionally expressed on peripheral sensory neurones mediate inflammatory hyperalgesia

Walker, Katharine; Reeve, Alya; Bowes, M; Winter, Janet; Wotherspoon, Glen; Davis, Andrew Jackson; Schmid, Peter; Gasparini, F.; Kühn, Rainer; Urbán, László

doi:10.1016/s0028-3908(00)00114-3

Cited by 214 publications

(158 citation statements)

References 42 publications

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“…Immunohistochemical analysis also revealed double labeling of DRG neurons with mGluR5 and TRPV1 (supplemental Fig. 6, available at www.jneurosci.org as supplemental material), which is consistent with the results of a previous report (Walker et al, 2001b).…”

Section: Discussionsupporting

confidence: 90%

“…Multiple inflammatory mediators have been shown to heighten the sensitivity of nociceptive sensory neurons after binding to their respective G-protein-coupled receptors (GPCRs) (Scholz and Woolf, 2002), leading to inflammationinduced thermal hyperalgesia via TRPV1. Group I metabotropic glutamate receptors (mGluRs) (especially mGluR5) are expressed together with TRPV1 in dorsal root ganglion (DRG) neurons (Walker et al, 2001b) and are also involved in peripheral sensitization of sensory neurons via G-protein-mediated TRPV1 modulation (Hu et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Membrane-Delimited Coupling of TRPV1 and mGluR5 on Presynaptic Terminals of Nociceptive Neurons

Kim¹,

Park²,

Back³

et al. 2009

J. Neurosci.

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Transient receptor potential vanilloid subtype 1 (TRPV1) and metabotropic glutamate receptor 5 (mGluR5) located on peripheral sensory terminals have been shown to play critical roles in the transduction and modulation of pain sensation. To date, however, very little is known regarding the significance of functional expression of mGluR5 and TRPV1 on the central terminals of sensory neurons in the dorsal horn of the spinal cord. Here we show that TRPV1 on central presynaptic terminals is coupled to mGluR5 in a membranedelimited manner, thereby contributing to the modulation of nociceptive synaptic transmission in the substantia gelatinosa neurons of the spinal cord. Further, our results demonstrate that TRPV1 is involved in the pain behaviors induced by spinal mGluR5 activation, and diacylglycerol produced by the activation of mGluR5 mediates functional coupling of mGluR5 and TRPV1 on the presynaptic terminals. Thus, mGluR5-TRPV1 coupling on the central presynaptic terminals of nociceptive neurons may be an important mechanism underlying central sensitization under pathological pain conditions.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Membrane-Delimited Coupling of TRPV1 and mGluR5 on Presynaptic Terminals of Nociceptive Neurons

Kim¹,

Park²,

Back³

et al. 2009

J. Neurosci.

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“…Subcutaneous administration of the selective group I mGlu agonist (R,S)-3,5-dihydroxy phenylglycine into the rodent hind paw results in enhanced sensitivity to thermal stimuli (Bhave et al, 2001) and intrathecal (R,S)-3,5-dihydroxy phenylglycine administration results in immediate spontaneous nociceptive behaviors in rodents. In addition, peripherally (Bhave et al, 2001;Walker et al, 2001;Zhu et al, 2005), intrathecally , and systemically (Zhu et al, 2004) administered antagonists of mGlu5 have been demonstrated to have analgesic properties in a variety of preclinical pain models.…”

mentioning

confidence: 99%

The Metabotropic Glutamate Receptor Subtype 5 Antagonist Fenobam Is Analgesic and Has Improved in Vivo Selectivity Compared with the Prototypical Antagonist 2-Methyl-6-(phenylethynyl)-pyridine

Montana

Cavallone²,

Stubbert³

et al. 2009

J Pharmacol Exp Ther

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Metabotropic glutamate receptor subtype 5 (mGlu5) has been demonstrated to play a role in the modulation of numerous nociceptive modalities. When administered via peripheral, intrathecal, or systemic routes, mGlu5 antagonists have analgesic properties in a variety of preclinical pain models. Despite a wealth of data supporting the use of mGlu5 antagonists to treat pain, studies have been limited to preclinical animal models due to a lack of mGlu5 antagonists that are approved for use in humans. It has been demonstrated previously that fenobam [N-(3-chlorophenyl)-NЈ-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea], an anxiolytic shown to be safe and effective in human trials, is a selective and potent noncompetitive antagonist of mGlu5 (J Pharmacol Exp Ther 315:711-721, 2005). Here, we report a series of studies aimed at testing whether fenobam, similar to the prototypical mGlu5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), has analgesic properties in mice. We show that fenobam reduces formalininduced pain behaviors and relieves established inflammationinduced thermal hypersensitivity in mice. Similar results were seen with MPEP. Administration of fenobam resulted in an increase in locomotor activity in the open-field task but did not impair performance on the accelerating Rotarod. Analysis of brain and plasma fenobam levels indicated that fenobam is rapidly concentrated in brain after intraperitoneal administration in mice but is essentially cleared from circulation within 1 h after injection. Fenobam had no analgesic effect in mGlu5 knockout mice, whereas the prototypical antagonist MPEP retained significant analgesic efficacy in mGlu5 knockouts. These results demonstrate that fenobam is analgesic in mice and has an improved in vivo selectivity for mGlu5 over MPEP.

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“…Futhermore, intraplantar injection of the specific Glu receptors agonists NMDA, AMPA or kainate results in mechanical hyperalgesia and allodynia that can be blocked by appropriate antagonists (Zhou et al, 1996). Hyperalgesia is induced by binding the released glutamate to NMDA receptor (Leem et al, 2001;Du et al, 2003), group I mGluR (Bhave et al, 2001;Zhou et al, 2001;Hu et al, 2002;Walker et al, 2001;Lee et al, 2007), but not group II mGluR (Yang and Gereau IV, 2003).…”

Section: Wwwintechopencommentioning

confidence: 99%

Interactions Between Glutamate Receptors and TRPV1 Involved in Nociceptive Processing at Peripheral Endings of Primary Afferent Fibers

Jin¹,

Takemura²,

Furuyama³

et al. 2012

Pharmacology

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mGlu5 receptors and nociceptive function II. mGlu5 receptors functionally expressed on peripheral sensory neurones mediate inflammatory hyperalgesia

Cited by 214 publications

References 42 publications

Membrane-Delimited Coupling of TRPV1 and mGluR5 on Presynaptic Terminals of Nociceptive Neurons

Membrane-Delimited Coupling of TRPV1 and mGluR5 on Presynaptic Terminals of Nociceptive Neurons

The Metabotropic Glutamate Receptor Subtype 5 Antagonist Fenobam Is Analgesic and Has Improved in Vivo Selectivity Compared with the Prototypical Antagonist 2-Methyl-6-(phenylethynyl)-pyridine

Interactions Between Glutamate Receptors and TRPV1 Involved in Nociceptive Processing at Peripheral Endings of Primary Afferent Fibers

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