This study provides the first demonstration that central
cannabinoids modulate the antinociceptive actions of
metabotropic glutamate receptors (mGluRs) on
formalin-induced temporomandibular joint (TMJ) nociception. Noxious scratching behavior induced by
formalin injection in the TMJ was used as a model of
pain. Intracisternal injection of 30mug of
WIN 55,212-2, a non-subtype selective
cannabinoid receptor agonist, attenuated the number of scratches by 75% as compared with the vehicle-treated group, whereas vehicle alone or 3 or 10 microg of
WIN 55,212-2 had no effect. To explore the postulated interaction between central
cannabinoid receptors and mGluRs, effects of combined administration of sub-
analgesic doses of
WIN 55,212-2 and group II or III mGluR agonists were tested. Group II or III mGluRs agonists were administered intracisternally 10 min after intracisternal administration of
WIN 55,212-2. Neither 100 nmol APDC, a group II mGluRs agonist, nor
L-AP4, a group III mGluR agonist, altered nociceptive behavior when given alone but significantly inhibited the
formalin-induced nociceptive behavior in the presence of a sub-threshold dose ( 3microg) of
WIN 55,212-2. The ED50 value of APDC or
L-AP4 was significantly reduced upon co-treatment with
WIN 55,212-2 than in the vehicle-treated group, highlighting the important therapeutic potential of the combined administration of group II or III mGluR agonists with
cannabinoids to effectively treat inflammatory
pain associated with the TMJ. Potentiating effects of group II or III mGluRs agonists will likely permit the administration of
cannabinoids at doses that do not achieve significant accumulation to produce undesirable motor dysfunction.