Involvement Of Adrenomedullin In The Development Of Morphine Tolerance And The Modulation Of Morphine Tolerance By MrgC Receptors

Opioids typified by morphine are the most effective analgesics for the treatment of severe pain. However, therapeutic usefulness of opioids is greatly limited by the development of tolerance that usually occurs following repeated use. Hence, it is necessary to investigate the mechanism of morphine tolerance. AM has an import role in the develepment of morphine tolerane. Analgesia efficacy induced by morphine will be prolonged when MrgC receptor is actived.The present study was designed to investigate mechanism of morphine tolerance and modulation effect of MrgC receptor on morphine tolerance. We found that the following results. (1) Intrathecal (i.t.) administration of AM22-52 inhibited the morphine-evoked alteration of μ-opioid receptors (MOR)-coupled G proteins. Chronic administration of AM for 9 days induced pERK and pCREB proteins, and alteration of MOR-coupled G proteins; Co-administration i.t. H89 or PD98059 with AM inhibited the alteration of MOR-coupled G proteins. The results suggest that enhanced bioactivity of the pronociceptive mediator AM induced the switch of Gi/o-protein to Gs-protein coupling by MOR via PKA-CREB- and ERK-dependent mechanisms contributing to the development of morphine tolerance. (2) The i.t administration of BAM8-22, an agoist of MrgC receptors, inhibited the up-regulation of IL-1β in the spinal cord and TLR4 in DRG, but failed to effect the activity of MMP-9 in both the spinal cord and DRG. It indicates that the MrgC receptors inhibit morphine tolerance specifically via suppressing IL-1 (3 the spinal cord and TLR4 in DRG, but not the activity of MMP-9.