mGlu5 receptors and nociceptive function II. mGlu5 receptors functionally expressed on peripheral sensory neurones mediate inflammatory hyperalgesia

Previous studies have demonstrated that the metabotropic glutamate receptor subtype 5 (mGlu5 receptor) is expressed in the cell bodies of rat primary afferent neurones. We have further investigated the function and expression of mGlu5 receptors in primary afferent neurones, and their role in inflamm atory nociception. Freund's complete adjuvant-induced inflammatory hyperalg esia of the rat hind paw was significantly reduced by intraplantar, but not by intracerebroventricular or intrathecal microinjection of the selective mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP). Phar macological comparison in vivo of the nociceptive effects of glutamate, and ionotropic and metabotropic glutamate (mGlu) receptor agonists applied to the rat hind paw, indicated that group I mGlu receptor agonists induce a do se-dependent decrease in paw withdrawal threshold (mechanical hyperalgesia) . Group I mGlu agonist-induced hyperalgesia was inhibited by co-microinject ion of MPEP, but not by the mGlu1 receptor antagonist (S)-4-carboxy-phenylg lycine (4-CPG). Carrageenan-induced inflammatory hyperalgesia was inhibited by pretreatment of the inflamed hind paw with MPEP, but not following MPEP injection into the contralateral hind paw. Dorsal horn neurones receiving peripheral nociceptive and non-nociceptive afferent input were recorded in anaesthetized rats following microinjection of CHPG into their peripheral r eceptive fields. CHPG significantly increased the frequency and duration of firing of dorsal horn wide dynamic range (WDR) neurones and this activity was prevented by co-administration of CHPG and MPEP into their receptive fi elds. Immunohistochemical experiments revealed the co-expression of mGlu5 r eceptor protein and beta III tubulin in skin from naive rats, indicating th e constitutive expression of mGlu5 receptors on peripheral neurones. Double -labelling of adult rat DRG cells with mGlu5 receptor and vanilloid recepto r subtype I antisera also supports the expression of mGlu5 receptors on per ipheral nociceptive afferents. These results suggest that mGlu5 receptors e xpressed on the peripheral terminals of sensory neurones are involved in no ciceptive processes and contribute to the hyperalgesia associated with infl ammation. (C) 2000 Elsevier Science Ltd. All rights reserved.