Activation of Mas Oncogene-Related G Protein-Coupled Receptors Inhibits Neurochemical Alterations in the Spinal Dorsal Horn and Dorsal Root Ganglia Associated with Inflammatory Pain in Rats

Mas oncogene-related G protein-coupled receptor C (MrgC) is unequally expressed in sensory ganglia and has been shown to modulate pathologic pain. This study investigated the mechanism underlying the effect of MrgC receptors on inflammatory pain. Intrathecal administration of the selective MrgC receptor agonist bovine adrenal medulla 8-22 (BAM8-22) (30 nmol) inhibited complete Freund's adjuvant-evoked hyperalgesia. This was associated with the inhibition of protein kinase C-gamma and phosphorylated extracellular signal-regulated protein kinase in the spinal cord and/or dorsal root ganglia (DRG). The complete Freund's adjuvant injection in the hindpaw induced an increase in G(q), but not G(i) and G(s), protein in the spinal dorsal horn. This increase was inhibited by the intrathecal administration of BAM8-22. The exposure of DRG cultures to bradykinin (10 mu M) and prostaglandin E2 (1 mu M) increased the expression of calcitonin gene-related peptide (CGRP) and neuronal nitric oxide synthase in small-and medium-sized neurons as well as the levels of CGRP, aspartate, and glutamate in the cultured medium. The bradykinin/prostaglandin E-2-induced alterations were absent in the presence of BAM8-22 (10 mu M). These results suggest that the activation of MrgC receptors can modulate the increase in the expression of CGRP and neuronal nitric oxide synthase as well as the release of CGRP and excitatory amino acids in DRG associated with inflammatory pain. This modulation results in the inhibition of pain hypersensitivity by suppressing the expression of G(q) protein and protein kinase C-gamma and extracellular signal-regulated protein kinase signaling pathways in the spinal cord and/or DRG. The present study suggests that MrgC receptors may be a novel target for relieving inflammatory pain.