title: Changes in cannabinoid receptor subtype 1 activity and interaction with metabotropic glutamate subtype 5 receptors in the periaqueductal gray-rostral ventromedial medulla pathway in a rodent neuropathic pain model.
abstract: This study analyzed the effect of intra-ventrolateral periaqueductal grey (VL PAG) cannabinoid receptor (CB) stimulation on pain responses and rostral ventromedial medulla (RVM) neural activity in the chronic constriction injury (CCI) model of neuropathic pain in rats. Interaction between CB1 and metabotropic glutamate 1 and 5 (mGlu(1)/mGlu(5)) receptors was also investigated together with the expression of the CB1 receptor associated Gαi3 and cannabinoid receptor interacting 1a (CRIP 1a) proteins and the endocannabinoid synthesising and hydrolysing enzymes. In rats not subjected to CCI-induced pain, intra-VL PAG (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55,212-2) (2-4-8 nmol), a CB receptor agonist, increased the tail flick latency and changed the ongoing activity of RVM OFF and the tail flick-related activity of the ON and OFF cells, accordingly. These effects were prevented by SR141716A and MPEP, selective CB(1) and mGlu(5) receptor antagonists, respectively, though not by CPCCOEt, a selective mGlu(1) receptor antagonist. A higher dose up to 16 nmol of WIN 55,212-2 was necessary to increase tail flick latency and change ON and OFF cell activity in CCI rats. Consistently, CCI rats showed a decrease in the expression of CB(1) receptors, NAPE-PLD, Gαi3 and CRIP 1a proteins;the expression of diacylglycerol lipase A (DAGLA) was increased while fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL) did not change. As in control rats, MPEP and SR141716A also blocked WIN 55,212-2- induced effects in CCI rats. These data demonstrate a down regulation of the endocannabinoid system and a functional interaction between mGlu(5) and CB(1) receptors for cannabinoid-mediated effect in the PAG-RVM pain circuitry in neuropathic pain inflicted rats.
authors.affiliation: Department of Experimental Medicine, Pharmacology Division, The Second University of Naples, via Costantinopoli 16, 80138 Naples, Italy.
authors.forename: Enza
authors.initials: E
authors.lastname: Palazzo
authors.forename: Livio
authors.initials: L
authors.lastname: Luongo
authors.forename: Giulia
authors.initials: G
authors.lastname: Bellini
authors.forename: Francesca
authors.initials: F
authors.lastname: Guida
authors.forename: Ida
authors.initials: I
authors.lastname: Marabese
authors.forename: Serena
authors.initials: S
authors.lastname: Boccella
authors.forename: Francesca
authors.initials: F
authors.lastname: Rossi
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.forename: Vito
authors.initials: V
authors.lastname: de Novellis
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D004195:Disease Models, Animal; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009437:Neuralgia / Q000378:metabolism*; D010487:Periaqueductal Gray / Q000187:drug effects / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077285:Rimonabant
chemical_list: D000700:Analgesics; D048588:Benzoxazines; D018691:Excitatory Amino Acid Antagonists; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C121465:6-methyl-2-(phenylethynyl)pyridine; D000077285:Rimonabant