Duel Modulation Effects Of MrgC Receptors On The Potency Of Morphine-induced Analgesia

Mrg (Mas-related genes) receptors are a large family of G protein-coupled receptors (GPCR) and were identified in2001. These receptors are exclusively expressed in small-or medium-sized neurons in dorsal root (DRG) and trigeminal ganglia, suggesting that they may be associated with pain processing. We demonstrated in these studies that intrathecal administration of Mrg receptor agonist BAM8-22in rats induced hyperalgesia after pretreatment with pertussis toxin but analgesia following an injection of the phospholipase C inhibitor U73122. Acute administration of BAM8-22remarkably enhanced the potency of morphine induced analgesia, while chronic administration of this peptide reduced it. Mrg receptors were found to be co-localized with μ opioid receptors in small-and medium-sized DRG neurons. Blockade Mrg receptor by antibody inhibited the development of morphine tolerance induced by chronic i.t. administration of morphine. The similar results were observed following the treatment with RNAi in the spinal cord. Neutralization of Mrg receptor endogenous ligand.BAM22also inhibited the development of morphine tolerance. These results suggest:(1) MrgC receptors are coupled with both Gi and Gq proteins and involved in pain modulation and processing, respectively.(2) MrgC receptors and μ-opioid receptors are co-localized in the small-and medium-sized DRG neurons. Acute activation of MrgC receptors modulates the function of μ-opioid receptors.(3) Repeated activation of MrgC receptors may be ascribed to the development of morphine tolerance.These novel suggestions extended our knowledge about physiological and pharmacological functions of MrgC receptors. This is the first study demonstrating a novel mechanism for the development of morphine tolerance.