Metabotropic Glutamate and Cannabinoid Receptor Crosstalk in Periaqueductal Grey Pain Processing

Abstract

Metabotropic glutamate (mGlu) and cannabinoid receptors are G-protein coupled receptors which have shown synaptic co-operation through small lipid messengers in the central nervous system (CNS). A functional interaction between these two receptor families could have a relevant potential in the treatment of CNS disorders, including chronic pain. Indeed, both mGlu and cannabinoid receptors play a crucial role in the neurobiology of pain and their simultaneous manipulation could lead to novel strategies in pain management. In particular, as both mGlu and cannabinoid receptors have been found in the periaqueductal gray (PAG), a crucial station in the pain modulatory system, these receptors could be a substrate for producing analgesia at this level. In this review we aim to briefly illustrate the role of mGlu and cannabinoid receptors in controlling nociceptive processes, some points of convergence, and their functional interaction in pain processing. Further insights into this functional linkage between the mGlu and cannabinoid receptors could pave the way to a new strategy for pain relief, such as a drug cocktail acting on cannabinoid/metabotropic glutamate receptors.Key Words: Periaqueductal grey, metabotropic glutamate receptors; cannabinoid receptors, pain. METABOTROPIC GLUTAMATE RECEPTORS AND PAINMetabotropic glutamate (mGlu) receptors play an important role in the modulation of nociceptive processing and central sensitisation associated with persistent and chronic pain at several levels in the CNS [29,42,67,68].Several studies have shown that mGlu receptors modulate nociception from peripheral terminals [5,10,67,98,104]. This may stimulate the search for peripherally active mGlu receptor ligands, which are devoid of central adverse effects [30]. A role for mGlu receptors in spinal nociceptive processing has been reported, with particular emphasis on group I mGlu receptors [13,20,69,70,100,101,102,103]. Stimulation of group I mGlu receptors at spinal level generally produces pro-nociceptive effects [31,100], although functional differences between mGlu 1 and mGlu 5 receptors in modulating pain are recently emerging at the same rate as new selective mGlu receptor ligands are developed [69,90,101]. Spinal group I mGlu receptors also play an important role in nociceptive hypersensitivity associated with inflammation [8,69,101]. Intrathecal application of group II and group III agonists inhibit nociceptive responses [20,70,91], which may reflect the inhibition of glutamate release from nerve endings. Upregulation of mGlu 3 mRNA in the spinal cord following hind paw inflammation has also been reported [6]. A role for supraspinal mGlu receptors in the modulation of pain is also emerging, mGlu receptors modulate nociceptive responses at the level of ventrobasal thalamus [83][84][85], dorsal raphe [72] and amygdala [32,33,48]. This review will *Address correspondence to these authors at Department of Experimental Medicine, Section of Pharmacology "L. Donatelli"-Faculty of Medicine and Surgery, Second Universi...

CRIP1a inhibits endocytosis of G‐protein coupled receptors activated by endocannabinoids and glutamate by a common molecular mechanism

“…In this context it is interesting that functional interactions between CB 1 R and the mGluR types 1, 2 and 5 were reported (Palazzos et al . ).…”

Dissecting the Signaling Pathways Involved in the Crosstalk between Metabotropic Glutamate 5 and Cannabinoid Type 1 Receptors

“…The analgesic effect of cannabinoids in the CNS is mainly mediated by CB 1 receptor expression in neural substrates involved in nociceptive neurotransmission, including the spinal dorsal horn, PAG, dorsal raphe nuclei, and thalamic ventroposterolateral nucleus (Martin et al, 1995). Group I mGlu receptors can modulate nociceptive responses in the spinal cord, ventrobasal thalamus, dorsal raphe, amygdala, and PAG (Young et al, 1997;Hama, 2003;Palazzos et al, 2006). Importantly, it has been shown that mGlu 5 and CB 1 receptors exhibit a functional interaction to modulate nociception in some of these brain substrates.…”

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