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Pain and Dependence
The properties and functions of µ-opioid receptors have been studied intensively with respect to the binding of endogenous or exogenous ligands. However, much less is known about the constitutive, ligand-independent, activation of opioid receptors. Working in mice, Corder et al. (p. 1394) observed the prolonged constitutive activation of µ-opioid receptors in the spinal dorsal horn after transient peripheral inflammation. The results suggest that constitutive activation of µ-opioid receptors depresses nociception—the perception of pain—for long periods of time and induces cellular and physical dependence on endogenous opioid signaling.
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 (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 process that generates endogenous opioid dependence. Tonic MORCA suppression of withdrawal hyperalgesia may prevent the transition from acute to chronic pain.