Group III mGluR7 and mGluR8 in the amygdala differentially modulate nocifensive and affective pain behaviors

The amygdala plays an important role in the emotional–affective component of pain and in pain modulation. Group III metabotropic glutamate receptors (mGluRs) regulate pain-related activity in the amygdala, but the behavioral consequence and contribution of individual subtypes are not known yet. This study determined the effects of mGluR7 and mGluR8 activation in the central nucleus of the amygdala (CeA) on nocifensive and affective pain responses and on pain-related anxiety-like behavior of adult rats. The pain state was induced by intraarticular injections of kaolin/carrageenan into one knee joint to produce a localized monoarthritis. Subtype-selective agonists were administered into the CeA by microdialysis in normal rats and in rats with arthritis. An mGluR7-selective agonist (N,N′-dibenzyhydryl-ethane-1,2-diamine dihydrochloride, AMN082, 25 μM) decreased spinal withdrawal reflex thresholds and increased audible and ultrasonic vocalizations evoked by brief (15 s) compression of the knee. AMN082 also decreased the open-arm preference in the elevated plus maze (EPM) test, suggesting anxiety-like behavior. In arthritic animals, however, AMN082 failed to modulate the increased spinal reflexes and vocalizations and anxiety-like behavior. An mGluR8-selective agonist (S-3,4-dicarboxyphenylglycine, S-3,4-DCPG, 10 μM) had no effect in normal animals but inhibited the increased spinal reflex responses and audible and ultrasonic vocalizations of arthritic rats. S-3,4-DCPG also increased the open-arm choices of arthritic rats, suggesting anxiolytic effects. The results suggest that under normal conditions mGluR7, but not mGluR8, facilitates pain responses and has anxiogenic properties whereas mGluR8, but not mGluR7, can inhibit nocifensive and affective behaviors and anxiety in a model of arthritic pain.