Constitutive μ-opioid receptor activity leads to long-term endogenous analgesia and dependence

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 μ-opioid receptor (MOR) constitutive activity (MOR_CA) 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, MOR_CA initiates both analgesic signaling and a compensatory opponent process that generates endogenous opioid dependence. Tonic MOR _CA suppression of withdrawal hyperalgesia may prevent the transition from acute to chronic pain.