Constitutive μ-Opioid Receptor Activity Leads to Long-Term Endogenous Analgesia and Dependence

• Published in: Science (American Association for the Advancement of Science) Vol. 341; no. 6152; pp. 1394 - 1399
• Main Authors: Corder, G., Doolen, S., Donahue, R. R., Winter, M. K., Jutras, B. L., He, Y., Hu, X., Wieskopf, J. S., Mogil, J. S., Storm, D. R., Wang, Z. J., McCarson, K. E., Taylor, B. K.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 20-09-2013
• Subjects: Activation; Acute Pain - metabolism; Adenosine Monophosphate - metabolism; Adenylyl Cyclases - metabolism; Analgesia; Animals; Behavioral neuroscience; Binding; Biological and medical sciences; Chronic Pain - metabolism; Disease Models, Animal; Freund's Adjuvant - pharmacology; Fundamental and applied biological sciences. Psychology; Horns; Hyperalgesia; Hyperalgesia - chemically induced; Hyperalgesia - metabolism; Isoflurane - pharmacology; Ligands; Male; Medical sciences; Mice; Naltrexone - analogs & derivatives; Naltrexone - pharmacology; Narcotics; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Nociceptive Pain - metabolism; Opiates; Opioid analgesics; Opioid receptors; Pain; Perception; Physical trauma; Receptors; Receptors, N-Methyl-D-Aspartate - metabolism; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - antagonists & inhibitors; Receptors, Opioid, mu - metabolism; Sensitization; Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors; Spinal cord; Spinal Cord - drug effects; Spinal Cord - metabolism; Substance Withdrawal Syndrome - metabolism; Vertebrates: nervous system and sense organs; Human; Nervous system diseases; Acute; Opioid receptor; μ Opioid receptor; Opiates; Glutamate receptor; Activation; Long term; Opioid peptide; Hyperalgesia; Analgesia; Pain; Animal; Dependence; Antagonist
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1239403

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, 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.