title: 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.
abstract: The metabotropic glutamate receptor 7 (mGluR7) negative allosteric modulator, 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP), was locally microinjected into the ventrolateral periaqueductal gray (VL PAG) and the effect on pain responses in formalin and spare nerve injury (SNI) -induced neuropathic pain models was monitored in the rat. The activity of rostral ventromedial medulla (RVM) "pronociceptive" ON and "antinociceptive" OFF cells was also evaluated. Intra-VL PAG MMPIP blocked the first and second phase of nocifensive behaviour in the formalin pain model. MMPIP increased the tail flick latency and simultaneously increased the activity of the OFF cells while inhibiting that of ON cells in rats with SNI of the sciatic nerve. MMPIP failed to modify nociceptive responses and associated RVM ON and OFF cell activity in sham rats. An increase in mGluR7 gene, protein and staining, the latter being associated with vesicular glutamate transporter-positive profiles, has been found in the VL PAG in SNI rats. Blockade of mGluR7 within the VL PAG has an antinociceptive effect in formalin and neuropathic pain models. VL PAG mGluR7 blockade offers a target for dis-inhibiting the VL PAG-RVM pathway and silencing pain in inflammatory and neuropathic pain models.
authors.affiliation: Department of Anaesthesiology, Surgery and Emergency, The Second University of Naples, Piazza Luigi Miraglia 2, Naples 80178, Italy. enza.palazzo@unina2.it.
authors.forename: Enza
authors.initials: E
authors.lastname: Palazzo
authors.forename: Ida
authors.initials: I
authors.lastname: Marabese
authors.forename: Livio
authors.initials: L
authors.lastname: Luongo
authors.forename: Serena
authors.initials: S
authors.lastname: Boccella
authors.forename: Giulia
authors.initials: G
authors.lastname: Bellini
authors.forename: Maria Elvira
authors.initials: ME
authors.lastname: Giordano
authors.forename: Francesca
authors.initials: F
authors.lastname: Rossi
authors.forename: Mariantonietta
authors.initials: M
authors.lastname: Scafuro
authors.forename: Vito de
authors.initials: Vd
authors.lastname: Novellis
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects* / Q000378:metabolism*; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism; D010487:Periaqueductal Gray / Q000187:drug effects* / Q000378:metabolism*; D011728:Pyridones / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C553164:6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazonolo(4,5-c)pyridin-4(5H)-one; D000700:Analgesics; D011728:Pyridones; D018094:Receptors, Metabotropic Glutamate; C102719:metabotropic glutamate receptor 7