There is pharmacological evidence Group II and III metabotropic glutamate receptors (mGluRs) function as activity-dependent autoreceptors, inhibiting transmission in supraspinal sites. These receptors are expressed by peripheral nociceptors. We investigated whether mGluRs function as activity-dependent autoreceptors inhibiting pain transmission to the rat CNS, particularly TRPV1-induced activity. Blocking peripheral mGluR activity by intraplantar injection of antagonists LY341495 (LY, 20, 100 μM, Group II/III ), APICA (100 μM, Group II) or UBP1112 (30 μM, Group III) increased capsaicin (CAP)-induced nociceptive behaviors and nociceptor activity. In contrast, Group II agonist APDC (0.1 μM) or Group III agonist L-AP4 (10 μM) blocked the LY-induced increase. Ca2+ imaging in dorsal root ganglion (DRG) cells confirmed LY enhanced CAP-induced Ca2+ mobilization which was blocked by APDC and L-AP4. We hypothesized that excess glutamate (GLU), released by high intensity and/or prolonged stimulation endogenously activated Group II/III, dampening nociceptor activation. In support of this, intraplantar GLU+LY produced heat hyperalgesia and exogenous GLU+LY applied to nociceptors produced enhanced nociceptor activity and thermal sensitization. Intraplantar formalin known to elevate extracellular GLU, enhanced pain behaviors in the presence of LY. LY alone produced no pain behaviors, no change in nociceptor discharge rate or heat-evoked responses and no change in cytosolic Ca2+ in DRG cells, demonstrating a lack of tonic inhibitory control. Group II/III mGluRs maintain an activity-dependent autoinhibition, capable of significantly reducing TRPV1-induced activity. They are endogenously activated following high frequency and/or prolonged nociceptor stimulation, acting as built-in negative modulators of TRPV1 and nociceptor function, reducing pain transmission to the CNS.