Supraspinal metabotropic glutamate receptor subtype 8: a switch to turn off pain
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Glutamate is the main excitatory neurotransmitter in the central nervous system and as such controls the majority of synapses. Glutamatergic neurotransmission is mediated via ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs). Signaling via mGluRs permits to finely tune, rather than turning on/off, the excitatory neurotransmission as the iGluRs do. Eight mGluRs (mGluR1-8) have been cloned so far, which have been divided into three groups based on sequence homology, pharmacological properties and second messenger signaling. mGluRs are widely expressed both on glia and neurons. On neurons they are located both at postsynaptic (group I) and presynaptic sites (group II and III). Group II and III mGluR stimulation reduces glutamate release, which can prove useful in pathological conditions characterized by elevated glutamatergic neurotransmission which include chronic pain. Indeed, mGluRs are widely distributed on pain neuraxis. The recent development of selective mGluR ligands has permitted investigating the individual role of each mGluR on pain control. The development of (S)-3,4-dicarboxyphenylglycine, a selective mGluR8 agonist, has revealed the mGluR8 role in inhibiting pain and its related affective consequences in chronic pain conditions. mGluR8 proved also to be overexpressed in pain controlling areas during pathological pain guaranteeing the availability of a switch for turning off abnormal pain. Thus, mGluR8 corresponds to an ideal target in designing novel analgesics. This review will focus on the novel insights into the mGluR8 role on pain control, with particular emphasis on the supraspinal descending pathway, an antinociceptive endogenous source, whose activation or disinhibition (via mGluR8) induces analgesia.
KeywordsGlutamate Chronic pain Metabotropic glutamate receptor 8 Antinociceptive descending pathway DHPG
Conflict of interest
The authors declare that they have no conflict of interest.
- de Novellis V, Mariani L, Palazzo E, Vita D, Marabese I, Scafuro M, Rossi F, Maione S (2005) Periaqueductal grey CB1 cannabinoid and metabotropic glutamate subtype 5 receptors modulate changes in rostral ventromedial medulla neuronal activities induced by subcutaneous formalin in the rat. Neuroscience 134:269–281PubMedCrossRefGoogle Scholar
- Marabese I, Rossi F, Palazzo E, de Novellis V, Starowicz K, Cristino L, Vita D, Gatta L, Guida F, Di Marzo V, Rossi F, Maione S (2007b) Periaqueductal gray metabotropic glutamate receptor subtype 7 and 8 mediate opposite effects on amino acid release, rostral ventromedial medulla cell activities, and thermal nociception. J Neurophysiol 98:43–53PubMedCrossRefGoogle Scholar
- Palazzo E, Marabese I, Soukupova M, Luongo L, Boccella S, Giordano C, de Novellis V, Rossi F, Maione S (2011) Metabotropic glutamate receptor subtype 8 in the amygdala modulates thermal threshold, neurotransmitter release, and rostral ventromedial medulla cell activity in inflammatory pain. J Neurosci 31:4687–4697PubMedCrossRefGoogle Scholar
- Palazzo E, Marabese I, Luongo L, Boccella S, Bellini G, Giordano ME, Rossi F, Scafuro M, de Novellis V, Maione S (2013) Effects of a metabotropic glutamate receptor subtype 7 negative allosteric modulator in the periaqueductal grey on pain responses and rostral ventromedial medulla cell activity in rat. Mol Pain 9:44–55PubMedCentralPubMedCrossRefGoogle Scholar
- Robbins MJ, Starr KR, Honey A, Soffin EM, Rourke C, Jones GA, Kelly FM, Strum J, Melarange RA, Harris AJ, Rocheville M, Rupniak T, Murdock PR, Jones DN, Kew JN, Maycox PR (2007) Evaluation of the mGlu8 receptor as a putative therapeutic target in schizophrenia. Brain Res 1152:215–227PubMedCrossRefGoogle Scholar
- Rossi F, Marabese I, De Chiaro M, Boccella S, Luongo L, Guida F, De Gregorio D, Giordano C, de Novellis V, Palazzo E, Maione S (2013) Dorsal striatum metabotropic glutamate receptor 8 affects nocifensive responses and rostral ventromedial medulla cell activity in neuropathic pain conditions. J NeurophysiolGoogle Scholar
- Tong Q, Kirchgessner AL (2003) Localization and function of metabotropic glutamate receptor 8 in the enteric nervous system. Am J Physiol Gastrointest Liver Physiol 285:992–1003Google Scholar