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

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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 (mGlu1/mGlu5) receptors was also investigated together with the expression of the CB1 receptor associated G??i3 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 CB1 and mGlu5 receptor antagonists, respectively, though not by CPCCOEt, a selective mGlu1 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 CB1 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 mGlu5 and CB1 receptors for cannabinoid-mediated effect in the PAG-RVM pain circuitry in neuropathic pain inflicted rats.



Keywords: Cronic constriction injury; Immunochemistry; ON and OFF cell; RT-PCR; RVM; Western blot; cannabinoid recepors; gray-rostral ventromedical medulla pathway; metabotropic glutamate receptors; microinjections; neuropathic pain; periaqueductal grey

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/187152712800269731

Affiliations: Department of Experimental Medicine, Pharmacology Division, The Second University of Naples, via Costantinopoli 16, 80138 Naples, Italy.

Publication date: March 1, 2012

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  • CNS & Neurological Disorders - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in neurological and central nervous system (CNS) disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in neurological and CNS disorders. As the discovery, identification, characterization and validation of novel human drug targets for neurological and CNS drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.

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