Medical Molecular Biology Commons^™

Constitutive Mu-Opioid Receptor Activity Leads To Long-Term Endogenous Analgesia And Dependence, Gregory Corder, Suzanne Doolen, Renee R. Donahue, Michele K. Winter, Brandon L. Jutras, Y He, X Hu, Joseph S. Wieskopf, Jeffrey S. Mogil, Daniel R. Storm, Z J. Wang, Kenneth E. Mccarson, Bradley K. Taylor

Renee R. Donahue

Opioid receptor antagonists increase hyperalgesia in humans and animals, which indicates that endogenous activation of opioid receptors provides relief from acute pain; however, the mechanisms of long-term opioid inhibition of pathological pain have remained elusive. We found that tissue injury produced m-opioid receptor (MOR) constitutive activity (MORCA) that repressed spinal nociceptive signaling for months. Pharmacological blockade during the posthyperalgesia state with MOR inverse agonists reinstated central pain sensitization and precipitated hallmarks of opioid withdrawal (including adenosine 3′,5′-monophosphate overshoot and hyperalgesia) that required N-methyl-D-aspartate receptor activation of adenylyl cyclase type 1. Thus, MORCA initiates both analgesic signaling and a compensatory opponent …